Heterocyclic NF-κB inhibitors

ABSTRACT

The present invention relates to compounds of the general formula (I) and salts and physiologically functional derivatives thereof, (I) wherein R 1  is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl; R 2  is independently —NR 3 R 4 , (II) or (III) R 3  is independently alkyl, cycloalkyl, alkoxy, alkylamine, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl, R 4  is independently alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R 5  is independently H, COR 6 , CO 2 R 6 , SOR 6 , SO 2 R 6 , SO 3 R 6 , alkyl, cycloalkyl, alkoxy, —NH 2 , alkylamine, —NR 7 COR 6 , halogen, —OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; R 6  is independently H, alkyl, cycloalkyl, —NH 2 , alkylamine, aryl or heteroaryl; R 7  is independently H, alkyl, cycloalkyl, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, aryl, or heteroaryl; p is 0, or 1; q is 0, or 1; X is CO, or SO 2 .

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a U.S. National Phase of International Patent Application SerialNo. PCT/EP2005/008261, filed Jul. 29, 2005 and claims priority toEuropean Patent Application 04022363.8, filed Sep. 20, 2004 and U.S.Provisional Application 60/612,794, filed on Sep. 27, 2004. Theseaforementioned applications are incorporated by reference in theirentireties.

FIELD OF THE INVENTION

The present invention relates to compounds of the general formula (I) ora salt or a physiologically functional derivative or a stereoisomerthereof, for use as a medicament. The compounds of the invention areexceptionally useful for the treatment of diseases associated withabnormal and hyperproliferation of cells in mammals, especially inhumans. In particular, they are useful for the treatment of diseasescharacterized by a hyperproliferation of T-cells.

The present invention relates to compounds which are suitable for thetherapy of diseases that can be treated by modulating cellular pathwaysin eukaryotes, e.g. cancer, immunological or inflammatory disorders, andviral infections, to further processes for the preparation of thesecompounds, and to their use.

The present invention also relates to novel heterocyclic compounds ofthe general formula (II) or (III) and salts thereof, to methods of usingsuch compounds in treating NF-κB pathway associated disorders such asimmunologic and oncologic disorders, and to pharmaceutical compositionscontaining such compounds.

T-cell homeostasis is critical for the maintenance of immune tolerance.Defects in T-cell homeostasis can lead to autoimmune pathology.Autoimmune diseases include a large spectrum of clinically distinctentities that share a common aetiology, a misguided, self-directedimmune response.

This immune response can also be the consequence of an organ transplant.

Evidence suggests a prime role of T-cell reactivity in autoimmunediseases. Measuring proliferative responses in T-lymphocytes is a widelyused assay to measure immune competence (Killestein, J. et al. J.Neuroimmunol. 133, 217-24, 2002).

We used a nonradioactive technique for the measurement of in vitroT-cell proliferation (Messele, T. et al. Clinical and DiagnosticLaboratory Immunology 687-692, 2000). Peripheral blood mononuclear cells(PBMCs) were isolated from human blood obtained from volunteer donators.PBMCs were isolated by centrifugation in ACCUSPIN tubes usingHISTOPAQUE.

PBMCs were stimulated with PHA and cell proliferation was measured witha Roche calorimetric BromUridin incorporation ELISA kit.

Regulation of the immune response is controlled by a variety ofsignalling pathways such as T-cell or TNF receptor signalling (Chen, G.et al. Science 296, 1634-1635, 2002). To further characterize targets ofcompounds which we found active in the T-cell proliferation assay, wetested the compounds on their ability to inhibit the human proteasome.

The major neutral proteolytic activity in the cytosol and nucleus is theproteasome, a 20S (700 kDa) particle with multiple peptidase activities.The continual turnover of cellular proteins by the ubiquitin-proteasomepathway is used by the immune system to screen for the presence ofabnormal intracellular proteins (Dantuma, N. P. et al. Nat. Biotechnol.2000, 18(5), 538-43; Goldberg, A L. et al. Nature 357, 375, 1993).

The ubiquitin-proteasome pathway plays an essential role in theregulation of NF-κB activity, being responsible for the degradation ofthe inhibitor IκB-α. In order to be targeted for degradation by theproteasome, IκB-α must first undergo selective phosphorylation at serineresidues 32 and 36, followed by ubiquitinylation (Chen, Z J. et al. Cell84, 853-862, 1996; Brown, K. et al. Science 267, 1485, 1995).

NF-κB, a transcription factor, regulates the transcription of animportant set of genes, involved in inflammatory responses (Baeuerle, PA. et al. Cell 87, 1, 13-20, 1996). Proteasome inhibitors block IκB-αdegradation and NF-κB activation (Traeckner et al. EMBO J. 113, 5433,1994).

Patents describing proteasome inhibitors have been described in reviews(Adams, J. et al. Ann. Rev. Med. Chem. 31, 279-288, 1996) and in U.S.Pat. Nos. 6,117,887, 5,834,487, WO 00/004954, WO 00/04954, WO 00/170204,WO 00/33654, WO 00/64863, WO 00/114324, WO 99/15183, WO 99/37666.

One such compound, named velcade (bortezomib), has been approved totreat multiple myeloma (Paramore, A. et al. Nature Reviews, 2, 611,2003).

Here we describe novel chemical entities with proteasome inhibitoryactivity.

NF-κB (Nuclear Factor-κB) is an eucariotic transcription factor of therel family, which is located in the cycloplasm in an inactive complex,as a homo- or heterodimer. Predominantly it exists as a heterodimercomposed of p50 and p65 subunits, bound to inhibitory proteins of theIκB family, usually IκB-α (D. Thanos et al., Cell 80, 529, 1995). NF-κBis activated in response to different stimuli, among which inflammatorycytokines, UV radiation, phorbol esters, bacterial and viral infections.Stimulation triggers the release of NF-κB from IκB in consequence of thephosphorylation and the following degradation of the IκB-α protein (P.A. Baeuerle et al., Annu. Rev. Immunol. 12, 141, 1995) by theproteasome. Once it is set free, NF-κB translocates in the nucleus whereit binds to the DNA at specific κB-sites and induces the transcriptionof a variety of genes encoding proteins involved in controlling theimmune and inflammatory responses, amongst others interleukins, TNF-α,the NO-synthase and the cyclooxigenase 2 (S. Grimm et al., J. Biochem.290, 297, 1993). Accordingly, NF-κB is considered an early mediator ofthe immune and inflammatory responses and it is involved in the controlof cell proliferation and in the pathogenesis of various human diseases,such as rheumatoid arthritis (H. Beker et al., Clin. Exp. Immunol. 99,325, 1995), ischemia (A. Salminen et al., Biochem. Biophys. Res. Comm.212, 939, 1995), arteriosclerosis (A. S. Baldwin, Annals Rev. Immunol.212, 649, 1996), as well as in the pathogenesis of AIDS.

Inhibition of NF-κB mediated gene transcription can be accomplishedthrough inhibition of phosphorylation of the inhibitory protein IκB,inhibition of IκB degradation, inhibition of NF-κB (p50/p65) nucleartranslocation, the inhibition of NF-κB-DNA binding or NF-κB-mediated DNAtranscription (J. C. Epinat et al., Oncogene 18, 6896, 1999).

There are several compounds that are known to inhibit NF-κB mediatedtranscriptional activation. Several different natural products such ascaffeic acid phenyl ester (1) (K. Natarajan et al., Proc. Natl. Acad.Sci. USA, 93, 9090, 1996), capsaicin (2) (S. Singh et al., J. Immunol.157, 4412, 1996) and N-acetylcysteine (3) (R. Pinkus et al., J. Biol.Chem. 271, 13422, 1996) have been shown to block NF-κB activation (FIG.1). Caffeic acid phenyl ester was shown to block NF-κB activation byTNF-α, phorbol ester, ceramide, hydrogen peroxide. This compound had noeffect on TNF-induced IκB degradation but prevented the translocation ofthe p65 subunit of NF-κB to the nucleus. Capsaicin blocked TNF-α andphorbol mediated NF-κB activation. This compound also blockeddegradation of IκB-α, and thus the nuclear translocation of NF-κB.

Helenalin (4), a sesquiterpene natural product, was shown to inhibitNF-κB activity by selectively alkylating the cysteine residue of the p65subunit of NF-κB (G. Lyss et al., J. Biol. Chem. 273, 33508, 1998 and P.Rungeler et al., Bioorg. Med. Chem. 7, 2343, 1999) (FIG. 2). Helenalin,however, did not inhibit neither IκB degradation nor NF-κBtranslocation. Lactacystin (5), also a natural product, inhibits both,20S and 26S proteasome (G. Fenteany et al., Science 268, 726, 1995)(FIG. 2). 26S proteasome is involved in degradation of phosphorylatedIκB. This compound has inhibitory activity on trypsin-like,chymotrypsin-like and peptidylglutamylpeptide hydrolyzing activities.

Several synthetic compounds such as pyrrolidine dithiocarbamate (6),nicotinamide (7), and 3-chloroprocainamide (8) were shown to beinhibitors of NF-κB transcritional activation (R. W. Pero et al., Mo.Cell. Biochem. 193, 119, 1999) (FIG. 3). These compounds blockedlipopolysacharide-induced TNF-α production in mouse in a dose dependentmanner. However, the exact site of activation of these compounds is notclear.

Celgene (Signal) introduced a novel class of quinazoline-pyrrolederivatives (9), which proved to be very potent inhibitors (up to 8 nM)of NF-κB mediated transcriptional activation (M. S. S. Palanki, Curr.Med. Chem. 9, 219, 2002).

In WO 2001068648 a series of β-carbolines were claimed with IC50 valuesup to 150 nM for compound 10, which blocked TNFα-induced IκBphosphorylation and degradation in HeLa cells (FIG. 5). The same classwas investigated by Millenium (A. B. Rabson, D. Weissmann, Clin. CancerRes. 11, 2, 2005).

Patent WO 04066996 discloses a novel class of imidazolidine basedcompounds (11), which show 88% NF-κB inhibition at a concentration of 1μM, with an IC₅₀ value of 0.3 μM (FIG. 6).

Presently only unsatisfactory therapies are established in this field,and therefore there still is a great need for new therapeutic agentsthat inhibit the NF-κB-pathway.

The novel compounds described herein are a new group of small moleculeinhibitors, which show an outstanding inhibition of the NF-κB-pathway.

The object of the present invention is solved by the subject-matter ofthe independent claims. Further advantageous features, aspects anddetails of the invention are evident from the dependent claims, thedescription, the figures, and the examples of the present application.

The present invention relates to compounds of the general formula (I) ora salt or a physiologically functional derivative or a stereoisomerthereof,

wherein

-   R¹ is independently hydrogen, alkyl, cycloalkyl, hydroxyalkyl,    haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl,    substituted heteroaryl, arylalkyl or substituted arylalkyl;-   R² is independently —NR³R⁴,

-   R³ is independently alkyl, cycloalkyl, alkoxy, alkylamine, —OH, —SH,    alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or    heteroaryl;-   R⁴ is independently alkyl, cycloalkyl, alkoxy, alkylamine,    alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or    heteroaryl;-   R⁵ is independently H, COR⁶, CO₂R⁶, SOR⁶, SO₂R⁶, SO₃R⁶, alkyl,    cycloalkyl, alkoxy, —NH₂, alkylamine, —NR⁷COR⁶, halogen, —OH, —SH,    alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or    heteroaryl;-   R⁶ is independently H, alkyl, cycloalkyl, —NH₂, alkylamine, aryl or    heteroaryl;-   R⁷ is independently H, alkyl, cycloalkyl, alkoxy, —OH, —SH,    alkylthio, hydroxyalkyl, aryl, or heteroaryl;-   p is 0, or 1;-   q is 0, or 1;-   X is CO or SO₂;    an alkyl group, if not stated otherwise, denotes a linear or    branched C₁-C₆-alkyl, preferably a linear or branched chain of one    to five carbon atoms, a linear or branched C₂-C₆-alkenyl or a linear    or branched C₂-C₆-alkinyl group, which can optionally be substituted    by one or more substituents R′;    the C₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkinyl residue may be    selected from the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C≡CH,    —C₃H₇, —CH(CH₃)₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C≡C—CH₃,    —CH₂—C≡CH, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁,    —C₆H₁₃, —C(R′)₃, —C₂(R′)₅, —CH₂—C(R′)₃, —C₃(R′)₇, —C₂H₄—C(R′)₃,    —C₂H₄—CH═CH₂, —CH═CH—C₂H₅, —CH═C(CH₃)₂, —CH₂—CH═CH—CH₃,    —CH═CH—CH═CH₂, —C₂H₄—C≡CH, —C≡C—C₂H₅, —CH₂—C≡C—CH₃, —C≡C—CH═CH₂,    —CH═CH—C≡CH, —C≡C—C≡CH, —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇,    —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃,    —C₃H₆—CH═CH₂, —CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃, —CH₂—CH═CH—C₂H₅,    —CH₂—CH═CH—CH═CH₂, —CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂,    —C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,    —CH₂—CH═C(CH₃)₂, C(CH₃)═C(CH₃)₂, —C₃H₆—C≡CH, —C≡C—C₃H₇,    —C₂H₄—C≡C—CH₃, —CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH═CH₂, —CH₂—CH═CH—C≡CH,    —CH₂—C≡C—C≡CH, —C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃, —C≡C—C≡C—CH₃,    —C≡C—CH₂—CH═CH₂, —CH═CH—CH₂—C≡CH, —C≡C—CH₂—C≡CH, —C(CH₃)═CH—CH═CH₂,    —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂, —C(CH₃)═CH—C≡CH,    —CH═C(CH₃)—C≡CH, —C≡C—C(CH₃)═CH₂, —C₃H₆—CH(CH₃)₂,    —C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,    —CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,    —CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,    —CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,    —CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂,    —C₂H₄—CH═C(CH₃)₂, —C₄H₈—C≡CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃,    —CH₂—C≡C—C₃H₇, —C₂H₄—C≡C—C₂H₅;    R′ is independently H, —CO₂R″, —CONHR″, —CR″O, —SO₂NR″,    —NR″—CO-haloalkyl, —NO₂, —NR″—SO₂-haloalkyl, —NR″—SO₂-alkyl,    —SO₂-alkyl, —NR″-CO-alkyl, —CN, alkyl, cycloalkyl, aminoalkyl,    alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl,    hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl    or heteroaryl;    R″ is independently H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl,    aryl, heteroaryl or aminoalkyl;    a cycloalkyl group denotes a non-aromatic ring system containing    three to eight carbon atoms, preferably four to eight carbon atoms,    wherein one or more of the carbon atoms in the ring can be    substituted by a group E, E being O, S, SO, SO₂, N, or NR″, R″ being    as defined above; the C₃-C₈-cycloalkyl residue may be selected from    the group comprising -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉,    -cyclo-C₆H₁₁, -cyclo-C₇H₁₃, -cyclo-C₈H₁₅, morpholine-4-yl,    piperazinyl, 1-alkylpiperazine-4-yl;    an alkoxy group denotes an O-alkyl group, the alkyl group being as    defined above; the alkoxy group is preferably a methoxy, ethoxy,    isopropoxy, t-butoxy or pentoxy group;    an alkylthio group denotes an S-alkyl group, the alkyl group being    as defined above;    an haloalkyl group denotes an alkyl group which is substituted by    one to five halogen atoms, the alkyl group being as defined above;    the haloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,    —CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂—C(R¹⁰)₃, —CH₂—CR¹⁰(R^(10′))₂,    —CH₂—CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇, or —C₂H₄—C(R¹⁰)₃, wherein R¹⁰,    R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;    a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group    being as defined above; an haloalkyloxy group denotes an alkoxy    group which is substituted by one to five halogen atoms, the alkyl    group being as defined above; the haloalkyloxy group is preferably a    —OC(R¹⁰)₃, —OCR¹⁰(R^(10′))₂, —OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅,    —OCH₂—C(R¹⁰)₃, —OCH₂—CR¹⁰(R^(10′))₂, —OCH₂—CR¹⁰(R^(10′))R^(10″),    —OC₃(R¹⁰)₇ or —OC₂H₄—C(R¹⁰)₃, wherein R¹⁰, R^(10′), R^(10″)    represent F, Cl, Br or I, preferably F;    a hydroxyalkylamino group denotes an (HO-alkyl)₂-N— group or    HO-alkyl-NH— group, the alkyl group being as defined above;    an alkylamino group denotes an HN-alkyl or N-dialkyl group, the    alkyl group being as defined above;    a halogen group is chlorine, bromine, fluorine or iodine;    an aryl group denotes an aromatic group having five to fifteen    carbon atoms, which can optionally be substituted by one or more    substituents R′, where R′ is as defined above; the aryl group is    preferably a phenyl group, -o-C₆H₄—R′, -m-C₆H₄—R′, -p-C₆H₄—R′,    1-naphthyl, 2-naphthyl, 1-anthracenyl or 2-anthracenyl;    a heteroaryl group denotes a 5- or 6-membered heterocyclic group    which contains at least one heteroatom like O, N, S. This    heterocyclic group can be fused to another ring. For example, this    group can be selected from a thiazol-2-yl, thiazol-4-yl,    thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,    1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl,    1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl,    1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,    1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl,    3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl,    3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,    2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,    4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,    1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, 2-indolyl,    3-indolyl, 2-indolinyl, 3-indolinyl, benzo[b]furanyl,    benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, quinazolinyl,    quinoxazolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,    tetrahydrothieno[3,4-d]imidazol-2-one,    pyrazolo[5,1-c][1,2,4]triazine, or tetrahydroisoquinolinyl group.    This heterocyclic group can optionally be substituted by one or more    substituents R′, wherein R′ is as defined above.

The invention also provides a pharmaceutical composition comprising acompound of formula (I), in free form or in the form of pharmaceuticallyacceptable salts and physiologically functional derivatives, togetherwith a pharmaceutically acceptable diluent or carrier therefore.

The term “physiologically functional derivative” as used herein refersto compounds which are not pharmaceutically active themselves but whichare transformed into their pharmaceutical active form in vivo, i.e. inthe subject to which the compound is administered. Examples ofphysiologically functional derivatives are prodrugs.

In addition, the present invention provides methods for preparing thecompounds of the invention such as compounds of formula (I).

The compounds of formula (I) may be obtained via various methods.

Piperidin-4-yl-thiazole-4-carboxamide can be prepared by various methodsdescribed in the literature. One such example is the oxidation of theappropriate 2,5-dihydrothiazoles as described in Houben-Weyl, 2002, 730.The dihydrothiazoles can also synthesised by methods described in thesame reference or described in You, S., Razavi, H., Kelly, J. W. Angew.Chem. 2003, 115, 87 or Katritzky, A R., Cai, C., Suzuki, K., Singh, S K.J. Org. Chem. 2004, 69, 811-814 and references in both papers.Alternative methods were described by Yasuchika, S. et. al.Heterocycles, Vol. 57, No. 5, 2002.

In a preferred embodiment of the invention, in the compounds of formula(I), R¹ is:

In a preferred embodiment of the invention, in the compounds of formula(I), R⁵ is:

In another preferred embodiment, in the compounds of formula (I), R³, R⁴and R⁷ is H.

In a preferred embodiment of the invention, in the compounds of formula(I), R² is:

In a preferred embodiment of the invention, in the compounds of formula(I), R¹ is substituted aryl, p is 0, q is 1, X is CO, and

R² is

In a preferred embodiment of the invention, in the compounds of formula(I), R¹ is benzyl, p is 0, q is 0, and

R² is

The present invention also relates to compounds of the general formula(III) or a salt or a physiologically functional derivative, or astereoisomer thereof,

wherein

-   R¹ is —C(O)R⁷, —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸,    —C(S)R⁷, or R¹ and R² together with the N-atom or the C-atom to    which they are attached form a 3 to 8 membered ring, wherein at    least one or more of the carbon atoms in the ring is a heteroatom    like O, N, S and the ring can be substituted by R⁹;-   R² is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl,    aryl or R² is absent in the case Z forms a ring together with R¹;-   R³ is H, —C(O)NR^(a)R^(b), halogen, alkyl, haloalkyl, aryl or    heteroaryl;-   R⁴ is H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, alkylaryl, or aryl;-   R⁵ is H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, alkylaryl, or aryl;-   R^(a) is H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, alkylaryl, or aryl;-   R^(b) independently represents H, —CN, —OH, —SH, —CO₂R^(4′),    —C(O)R^(4′), —SO₂NR^(4′), —NR^(4′)R^(5′), —C(O)NR⁷R⁸, —SO₂-alkyl,    —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),    —NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl,    —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heterocycle,    alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen,    haloalkyl, haloalkyloxy, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benz-oxazolyl, hydroxyalkyl, hydroxycycloalkyl,    hydroxyalkylamino, aryl, arylalkyl or a heterocycle;-   R^(4′), R^(4″), R^(5′) independently are H, halogen, alkyl,    —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, haloalkyl, —CH₂)_(p)NR⁷R⁸,    —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl,    or aryl;-   R⁷, R^(7′), R⁸ independently are H, halogen, alkyl, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, alkylaryl, or aryl;-   A is CO or SO₂;-   X is NR^(2′), O, S, or CR^(2′);-   Z is N or CR^(2′); if Z is CH then X is O or NR^(2′)-   R^(2′) is H, alkyl, —C(O)NR², —C(O)R^(b), cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, alkylaryl, or aryl;-   p is 1 to 6;-   q is 1 to 6;-   r is 0, or 1;-   R⁹ independently represents H, —CN, —OH, —SH, alkoxy, alkylthio,    —CO₂R^(4′), —C(O)R^(4′), —C(O)NR⁷R⁸, —SO₂NR^(4′), —NR^(4′)R^(5′),    —SO₂-alkyl, —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′),    —NR^(4′)C(O)R^(4″), —NR^(4′)—CO-haloalkyl, —NO₂,    —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl,    —NR^(4′)(CH₂)_(p)heterocycle, alkyl, hydroxyalkyl, cycloalkyl,    alkylamino, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,    —C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,    —C(NR^(4″))NR^(4′)benzoxazolyl, hydroxycycloalkyl,    hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl    or a heterocycle;-   R^(4′), R^(4″), R^(5′) independently are H, halogen, alkyl,    —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, hydroxyalkyl, —CH₂)_(p)NR⁷R⁸,    —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl,    haloalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or    aryl;    wherein    an alkyl group, if not stated otherwise, denotes a linear or    branched C₁-C₆-alkyl, preferably a linear or branched chain of one    to six carbon atoms, a linear or branched C₂-C₆-alkenyl or a linear    or branched C₂-C₆-alkynyl group, which can be substituted by one or    more substituents R⁹; R⁹ being defined as above.    a heterocycle denotes a heterocycloalkyl group or a heteroaryl    group;    a cycloalkyl group denotes a non-aromatic ring system containing    three to eight carbon atoms, preferably four to eight carbon atoms,    wherein one or more of the carbon atoms in the ring can be    substituted by a group R⁹ being as defined above; the    C₃-C₈-cycloalkyl residue may be selected from the group comprising    -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃,    -cyclo-C₈H₁₅;    a heterocycloalkyl group denotes a non-aromatic ring system    containing two to ten carbon atoms and at least one heteroatom like    O, N, or S, wherein one or more of the carbon atoms in the ring can    be substituted by R⁹ being as defined above; preferred    heterocycloalkyl groups are morpholine-4-yl, piperazinyl,    1-alkylpiperazine-4-yl, piperidinyl, pyrrolidinyl, azepane-1-yl;    an alkoxy group denotes an O-alkyl group, the alkyl group being as    defined above; the alkoxy group is preferably a methoxy, ethoxy,    isopropoxy, t-butoxy or pentoxy group;    an alkylthio group denotes an S-alkyl group, the alkyl group being    as defined above;    an haloalkyl group denotes an alkyl group which is substituted by    one to five halogen atoms, the alkyl group being as defined above;    the haloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,    —CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂C(R¹⁰)₃, —CH₂CR¹⁰(R^(10′))₂,    —CH₂CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇, or —C₂H₄C(R¹⁰)₃, wherein R¹⁰,    R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;    a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group    being as defined above;    an haloalkyloxy group denotes an alkoxy group which is substituted    by one to five halogen atoms, the alkyl group being as defined    above; the haloalkyloxy group is preferably a —OC(R¹⁰)₃,    —OCR¹⁰(R^(10′))₂, —OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂C(R¹⁰)₃,    —OCH₂CR¹⁰(R^(10′))₂, —OCH₂CR¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇, or    —OC₂H₄C(R¹⁰)₃, wherein R¹⁰, R^(10′), R^(10″) represent F, Cl, Br or    I, preferably F;    a hydroxyalkylamino group denotes an (HO-alkyl)₂-N— group or    HO-alkyl-NH— group, the alkyl group being as defined above;    an alkylamino group denotes an HN-alkyl or N-dialkyl group, the    alkyl group being as defined above;    a halogen group is fluorine, chlorine, bromine, or iodine;    an aryl group denotes an aromatic group having five to fifteen    carbon atoms, which can be substituted by one or more substituents    R⁹, where R⁹ is as defined above; the aryl group is preferably a    phenyl group, -o-C₆H₄—R⁹, -m-C₆H₄—R⁹, -p-C₆H₄—R⁹, 1-naphthyl,    2-naphthyl, 1-anthracenyl or 2-anthracenyl, R⁹ being as defined    above;    a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic    group which contains at least one heteroatom like O, N, S. This    heterocyclic group can be fused to another ring. For example, this    group can be selected from a thiazol-2-yl, thiazol-4-yl,    thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,    1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl,    1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl,    1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,    1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl,    3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl,    3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,    2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,    4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,    1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, 2-indolyl,    3-indolyl, 2-indolinyl, 3-indolinyl, benzo[b]furanyl,    benzo[b]thiophenyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,    quinazolinyl, quinoxazolinyl, quinolinyl, tetrahydroquinolinyl,    isoquinolinyl, or tetrahydroisoquinolinyl group. This heterocyclic    group or the fused ring can both be substituted independently by one    or more substituents R⁹, wherein R⁹ is as defined above;    a alkylaryl or arylalkyl group denotes an alkyl group (see def.    ‘alkyl’), which is bound to an aryl fragment (see def. ‘aryl’) via a    single bond. The linkage to the central moiety might occur over the    alkyl part or the aryl part.

The present invention relates also to compounds of the general formula(II) or a salt or a physiologically functional derivative, or astereoisomer thereof,

wherein

-   R¹ is —C(O)R⁷, —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸,    —C(S)R⁷, or R¹ and R² together with the N-atom or the C-atom to    which they are attached form a 3 to 8 membered ring, wherein at    least one or more of the carbon atoms in the ring is a heteroatom    like O, N, S and the ring can be substituted by R⁹;-   R² is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl,    aryl or R² is absent in the case Z forms a ring together with R¹;-   R³ is H, —C(O)NR⁴R⁹, halogen, alkyl, haloalkyl, aryl or heteroaryl;-   R⁶ is H, halogen, —C(O)R⁷, —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷,    —R⁷C(O)R⁸, —C(S)R⁷, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl,    —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R^(7′), alkyl,    cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,    hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or aryl;-   R⁷, R^(7′), R⁸ independently are H, halogen, alkyl, cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, —NHaryl, heteroaryl, alkylaryl, or aryl;-   A is CO or SO₂;-   X is NR^(2′), O, S, or CR^(2′);-   Y is N, O, or CR^(2′);-   Z is N or CR^(2′); if Z is CH then X is O or NR^(2′)-   R^(2′) is H, alkyl, —C(O)NR², —C(O)R^(b), cycloalkyl,    heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino,    alkylamino, heteroaryl, alkylaryl, or aryl;-   n is 0 to 2;-   p is 1 to 6;-   q is 1 to 6;-   r is 0, 1;    R⁹ independently represents H, —CN, —OH, —SH, —CO₂R^(4′),    —C(O)R^(4′), —C(O)NR⁷R⁸, —SO₂NR^(4′), —NR^(4′)R^(5′), —SO₂-alkyl,    —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),    —NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl,    —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heterocycle,    alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio,    —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃, —C(NR^(4″))NR^(4′)benzimidazolyl,    —C(NR^(4″))NR^(4′)benzthiazolyl, —C(NR^(4″))NR^(4′)benzoxazolyl,    hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen,    haloalkyl, haloalkyloxy, aryl, arylalkyl or a heterocycle;    R^(4′), R^(4″), R^(5′) independently are H, halogen, alkyl,    —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸,    —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl, haloalkyl,    hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl,    or aryl;    wherein    an alkyl group, if not stated otherwise, denotes a linear or    branched C₁-C₆-alkyl, preferably a linear or branched chain of one    to six carbon atoms, a linear or branched C₂-C₆-alkenyl or a linear    or branched C₂-C₆-alkynyl group, which can be substituted by one or    more substituents R⁹; R⁹ being defined as above.    a heterocycle denotes a heterocycloalkyl group or a heteroaryl    group;    a cycloalkyl group denotes a non-aromatic ring system containing    three to eight carbon atoms, preferably four to eight carbon atoms,    wherein one or more of the carbon atoms in the ring can be    substituted by a group R⁹ being as defined above; the    C₃-C₈-cycloalkyl residue may be selected from the group comprising    -cyclo-C₃H₅, -cyclo-C₄H₇, -cyclo-C₅H₉, -cyclo-C₆H₁₁, -cyclo-C₇H₁₃,    -cyclo-C₈H₁₅;    a heterocycloalkyl group denotes a non-aromatic ring system    containing two to ten carbon atoms and at least one heteroatom like    O, N, or S, wherein one or more of the carbon atoms in the ring can    be substituted by R⁹ being as defined above; preferred    heterocycloalkyl groups are morpholine-4-yl, piperazinyl,    1-alkylpiperazine-4-yl, piperidinyl, pyrrolidinyl, azocane-1-yl;    an alkoxy group denotes an O-alkyl group, the alkyl group being as    defined above; the alkoxy group is preferably a methoxy, ethoxy,    isopropoxy, t-butoxy or pentoxy group;    an alkylthio group denotes an S-alkyl group, the alkyl group being    as defined above;    an haloalkyl group denotes an alkyl group which is substituted by    one to five halogen atoms, the alkyl group being as defined above;    the haloalkyl group is preferably a —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,    —CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰)₅, —CH₂C(R¹⁰)₃, —CH₂CR¹⁰(R^(10′))₂,    —CH₂CR¹⁰(R^(10′))R^(10″), —C₃(R¹⁰)₇, or —C₂H₄C(R¹⁰)₃, wherein R¹⁰,    R^(10′), R^(10″) represent F, Cl, Br or I, preferably F;    a hydroxyalkyl group denotes an HO-alkyl group, the alkyl group    being as defined above;    an haloalkyloxy group denotes an alkoxy group which is substituted    by one to five halogen atoms, the alkyl group being as defined    above; the haloalkyloxy group is preferably a —OC(R¹⁰)₃,    —OCR¹⁰(R^(10′))₂, —OCR¹⁰(R^(10′))R^(10″), —OC₂(R¹⁰)₅, —OCH₂C(R¹⁰)₃,    —OCH₂CR¹⁰(R^(10′))₂, —OCH₂CR¹⁰(R^(10′))R^(10″), —OC₃(R¹⁰)₇, or    —OC₂H₄C(R¹⁰)₃, wherein R¹⁰, R^(10′), R^(10″) represent F, Cl, Br or    I, preferably F;    a hydroxyalkylamino group denotes an (HO-alkyl)₂-N— group or    HO-alkyl-NH— group, the alkyl group being as defined above;    an alkylamino group denotes an HN-alkyl or N-dialkyl group, the    alkyl group being as defined above;    a halogen group is fluorine, chlorine, bromine, or iodine;    an aryl group denotes an aromatic group having five to fifteen    carbon atoms, which can be substituted by one or more substituents    R⁹, where R⁹ is as defined above; the aryl group is preferably a    phenyl group, -o-C₆H₄—R⁹, -m-C₆H₄—R⁹, -p-C₆H₄—R⁹, 1-naphthyl,    2-naphthyl, 1-anthracenyl or 2-anthracenyl, R⁹ being as defined    above;    a heteroaryl group denotes a 5- to 10-membered aromatic heterocyclic    group which contains at least one heteroatom like O, N, S. This    heterocyclic group can be fused to another ring. For example, this    group can be selected from a thiazol-2-yl, thiazol-4-yl,    thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,    1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl,    1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl,    1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,    1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl,    3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl,    3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,    2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,    4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,    1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, 2-indolyl,    3-indolyl, 2-indolinyl, 3-indolinyl, benzo[b]furanyl,    benzo[b]thiophenyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,    quinazolinyl, quinoxazolinyl, quinolinyl, tetrahydroquinolinyl,    isoquinolinyl, or tetrahydroisoquinolinyl group. This heterocyclic    group or the fused ring can both be substituted independently by one    or more substituents R⁹, wherein R⁹ is as defined above;    a alkylaryl or arylalkyl group denotes an alkyl group (see def.    ‘alkyl’), which is bound to an aryl fragment (see def. ‘aryl’) via a    single bond. The linkage to the central moiety might occur over the    alkyl part or the aryl part.

A preferred embodiment of the invention, in the compounds of formula(III), are compounds of the formula (IIIa),

whereinR¹ is COR⁷; R² and R³ is H; A is CO;R⁴, R⁵, R⁷ are defined as above; r is 1;X is O or S; and Z is as defined as above.

Another preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIIa), with R⁷═—NH-aryl.

Another preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIIb),

whereinR⁴ and R³ is H; A is CO; R⁵ is defined as above; X is O or S; r is 1;Z forms together with R¹ a 6-membered ring and R² is absent;if Z is N then X is O or S, or if Z is CR^(2′), X is O;Y′ is O or NR^(2′), R^(2′) is as defined above;

Another preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIIc),

whereinR¹ is COR⁷; wherein R⁷ is phenyl and R¹¹, R¹² independently represent H,—CN, —OH, —SH, —CO₂R^(4′), —C(O)R^(4′), —SO₂NR^(4′), —NR^(4′)R^(5′),—SO₂-alkyl, —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),—NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl,—NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heterocycle, alkyl, cycloalkyl,alkylamino, alkoxy, alkylthio, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,—C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,—C(NR^(4″))NR^(4′)benzoxazolyl hydroxyalkyl, hydroxycycloalkyl,hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl ora heterocycle; and R^(4′), R^(4″), R^(5′) are defined as above;r is 1; Z is N, R² and R³ is H; X is O or S, A is CO;R⁴ is defined as above, R⁵ is C(NR⁷)NR^(7′)R⁸,R⁷ and R^(7′) are defined as above, R⁸ is a heterocycloalkyl wherein Y″is O, S or NR^(2′) and R^(11′), R^(12′) independently represents H, —CN,—OH, —SH, —CO₂R^(4′), —C(O)R^(4′), —SO₂NR^(4′), —NR^(4′)R^(5′),—SO₂-alkyl, —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),—NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl,—NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heterocycle, alkyl, cycloalkyl,alkylamino, alkoxy, alkylthio, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,—C(NR^(4″))NR^(4′)-benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,—C(NR^(4″))NR^(4′)benzoxazolyl hydroxyalkyl, hydroxycycloalkyl,hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl ora heterocycle; and R^(4′), R^(4″), R^(5′) are defined as above;

A more preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIId),

whereinZ forms together with R¹ a 6-membered ring and R² is absent;Z is N, and R³ is H; X is O or S, A is CO;R⁴ is defined as above, R⁵ is C(NR⁷)NR^(7′)R⁸,R⁷ and R^(7′) are defined as above,R⁸, Y″ and R^(11′), R^(12′) are defined as above under formula (IIIc),r is 1; Y′ is O or NR^(2′) and R^(2′) is as defined above.

Another more preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIIe),

whereinZ forms together with R¹ a 6-membered ring and R² is absent;r is 1; R³, R⁴ and R⁵ are defined as above, A is CO; X is O or S,R¹¹ and R¹² are defined as above under formula (IIIc), andif Z is N, X is O or S, if Z is CH, X is O.

Another more preferred embodiment of the invention, in the compounds offormula (III), are compounds of the formula (IIIf),

whereinZ forms together with R¹ a 6-membered ring and R² is absent;Z is N or CH, and R³ is H; X is O or S, A is CO;R⁴ is defined as above, R⁵ is C(NR⁷)NR^(7′)R⁸,R⁷ and R^(7′) are defined as above,R⁸, Y″ and R¹¹, R^(11′), R¹², R^(12′) are defined as above under formula(IIIc),r is 1; Y′ is O or NR^(2′) and R^(2′) is as defined above.

A preferred embodiment of the invention, in the compounds of formula(II), are compounds of the formula (IIa),

whereinR¹ and R² are defined as above, Z is defined as above.r is 1; A is CO; X is O or S, R³ is H, Y is NR^(2′) wherein R^(2′) isphenyl and R¹¹ and R¹² are defined as above under formula (IIIc).

A more preferred embodiment of the invention, in the compounds offormula (II), are compounds of the formula (IIb),

whereinR¹ and R² are defined as above, Z is defined as above.r is 1; A is CO; X is O or S, R³ is H,Y is NR^(2′)wherein R^(2′) is phenyl and R¹¹ is H and R¹² is CF₃.

Another more preferred embodiment of the invention, in the compounds offormula (II), are compounds of the formula (IIc),

whereinZ forms together with R¹ a 6-membered ring and R² is absent; A is CO;r is 1; X is O or S, R³ is H, Y′ is NR^(2′).

Another more preferred embodiment of the invention, in the compounds offormula (II), are compounds of the formula (IId),

whereinZ is defined as above;R³ is H, Y′ is NR^(2′). R^(2′) is as defined above;R¹¹, R^(11′) and R¹², R^(12′) are defined as above.

The compounds of formula (III) and (II) may be obtained via variousmethods. One possibility for the synthesis of compounds of formula(IIIa, c and IIa, b) (see scheme 1) comprises a step of reacting acompound of formula (V) with a compound of formula (VI) under classicalamide coupling conditions, like e.g. HBTU, iPr₂NEt, DMF, 0° C. to r.t.to obtain intermediate (VII). Another alternative for this step might bethe reaction of (V) with the corresponding acid chloride of (VI) toyield (VII). In a second step, compound (VII) is saponified with a 1 MNaOH solution, obtaining the expected acid (VIII) in almost quantitativeyield. This step could be realized under acidic conditions as well.Finally, another amide coupling step (with primary or secondary amines),which works similarity to step 1 described above, completes thesynthesis for compounds of type (IIIa, c and IIa, and b).

Compounds dealing with structure (IIIb, d, e, f) and (IIc, d) can besynthesized according to the procedure displayed in scheme 2. Herein, aheterocycle (IX) is reacted with a bromocompound (X), by means of anucleophilic substitution reaction, to gain a bicyclic ester (XI), whichis then saponified under standard and well-known conditions to acid(XII), completing the synthesis with another coupling step as describedin scheme 1 above.

In case of Z═CH, structure (IIIb, d, e, f) and (IIc, d) type compoundscan easily be synthesized following a protocol outlined in scheme 3,wherein a heterocycle (XIII) is converted to compound (XV) by acyclokondensation step. After saponification, (XVI) is coupled with anamine to yield the desired product (IIIb, d, e, f) or (IIc, d).

The compounds of the formula (I), (II) or (III) to be used according tothe invention can form salts with inorganic or organic acids or bases.Examples of pharmaceutically acceptable salts comprise withoutlimitation non-toxic inorganic or organic salts such as acetate derivedfrom acetic acid, aconitate derived from aconitic acid, ascorbatederived from ascorbic acid, benzoate derived from benzoic acid,cinnamate derived from cinnamic acid, citrate derived from citric acid,embonate derived from embonic acid, enantate derived from heptanoicacid, formiate derived from formic acid, fumarate derived from fumaricacid, glutamate derived from glutamic acid, glycolate derived fromglycolic acid, chloride derived from hydrochloric acid, bromide derivedfrom hydrobromic acid, lactate derived from lactic acid, maleate derivedfrom maleic acid, malonate derived from malonic acid, mandelate derivedfrom mandelic acid, methanesulfonate derived from methanesulfonic acid,naphtaline-2-sulfonate derived from naphtaline-2-sulfonic acid, nitratederived from nitric acid, perchlorate derived from perchloric acid,phosphate derived from phosphoric acid, phthalate derived from phthalicacid, salicylate derived from salicylic acid, sorbate derived fromsorbic acid, stearate derived from stearic acid, succinate derived fromsuccinic acid, sulphate derived from sulphuric acid, tartrate derivedfrom tartaric acid, toluene-p-sulfate derived from p-toluene-sulfonicacid and others. Such salts can be produced by methods known to someoneof skill in the art and described in the prior art.

Other salts like oxalate derived from oxalic acid, which is notconsidered as pharmaceutically acceptable can be appropriate asintermediates for the production of compounds of the formula (I), (II)or (III) or a pharmaceutically acceptable salt thereof orphysiologically functional derivative or a stereoisomer thereof.

The invention also provides a pharmaceutical composition comprising acompound of formula (I), (II) or (III), in free form or in the form ofpharmaceutically acceptable salts and physiologically functionalderivatives, together with a pharmaceutically acceptable diluent orcarrier therefore.

The term “physiologically functional derivative” as used herein refersto compounds which are not pharmaceutically active themselves(‘prodrugs’) but which are transformed into their pharmaceutical activeform in vivo, i.e. in the subject to which the compound is administered.

The compounds according to the invention and medicaments preparedtherewith are generally useful for the treatment of cell proliferationdisorders, for the treatment or prophylaxis of immunological diseasesand conditions (as for instance inflammatory diseases,neuroimmunological diseases, autoimmune diseases or other).

The compounds of the present invention are useful for the treatment ofdiseases which are caused by malignant cell proliferation, such as allforms of solid tumors, leukemias and lymphomas. Therefore the compoundsaccording to the invention and medicaments prepared therewith aregenerally useful for regulating cell activation, cell proliferation,cell survival, cell differentiation, cell cycle, cell maturation andcell death or to induce systemic changes in metabolism such as changesin sugar, lipid or protein metabolism. They can also be used to supportcell generation poiesis, including blood cell growth and generation(prohematopoietic effect) after depletion or destruction of cells, ascaused by, for example, toxic agents, radiation, immunotherapy, growthdefects, malnutrition, malabsorption, immune dysregulation, anemia andthe like or to provide a therapeutic control of tissue generation anddegradation, and therapeutic modification of cell and tissue maintenanceand blood cell homeostasis.

These diseases and conditions include but are not limited to cancer ashematological (e.g. leukemia, lymphoma, myeloma) or solid tumors (forexample breast, prostate, liver, bladder, lung, esophageal, stomach,colorectal, genitourinary, gastrointestinal, skin, pancreatic, brain,uterine, colon, head and neck, cervical, and ovarian, melanoma,astrocytoma, small cell lung cancer, glioma, basal and squameous cellcarcinoma, sarcomas as Kaposi's sarcoma and osteosarcoma) or for thetreatment of diseases which are cured or relieved by the inhibition ofone or several kinases and/or phosphatases.

“Treatment” according to the present invention is intended to meancomplete or partial healing of a disease, or alleviation of a disease orstop of progression of a given disease.

Thus, in one embodiment, the invention relates to the use of thecompounds of the formula (I), (II), and (III) or a pharmaceuticallyacceptable salt or physiologically functional derivative or astereoisomer thereof if desired with appropriate adjuvants and additivesfor the production of a medicament for the treatment or prevention of adisease characterized by hyperproliferation of keratinocytes and/or Tcells, especially inflammatory disorders and immune disorders,preferably selected from the group consisting of Addison's disease,alopecia areata, Ankylosing spondylitis, haemolytic anemia (anemiahaemolytica), pernicious anemia (anemia perniciosa), aphthae, aphthousstomatitis, arthritis, arteriosclerotic disorders, osteoarthritis,rheumatoid arthritis, aspermiogenese, asthma bronchiale, auto-immuneasthma, auto-immune hemolysis, Bechet's disease, Boeck's disease,inflammatory bowel disease, Burkitt's lymphoma, Crohn's disease,chorioiditis, colitis ulcerosa, Coeliac disease, cryoglobulinemia,dermatitis herpetiformis, dermatomyositis, insulin-dependent type Idiabetes, juvenile diabetes, idiopathic diabetes insipidus,insulin-dependent diabetes mellisis, autoimmune demyelinating diseases,Dupuytren's contracture, encephalomyelitis, encephalomyelitis allergica,endophthalmia phacoanaphylactica, enteritis allergica, autoimmuneenteropathy syndrome, erythema nodosum leprosum, idiopathic facialparalysis, chronic fatigue syndrome, febris rheumatica, glomerulonephritis, Goodpasture's syndrome, Graves' disease, Harnman-Rich'sdisease, Hashimoto's disease, Hashimoto's thyroiditis, sudden hearingloss, sensoneural hearing loss, hepatitis chronica, Hodgkin's disease,haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, iritis,leucopenia, leucemia, lupus erythematosus disseminatus, systemic lupuserythematosus, cutaneous lupus erythematosus, lymphogranuloma malignum,mononucleosis infectiosa, myasthenia gravis, traverse myelitis, primaryidiopathic myxedema, nephrosis, ophthalmia symphatica, orchitisgranulomatosa, pancreatitis, pemphigus, pemphigus vulgaris,polyarteritis nodosa, polyarthritis chronica primaria, polymyositis,polyradiculitis acuta, psoriasis, purpura, pyoderma gangrenosum,Quervain's thyreoiditis, Reiter's syndrome, sarcoidosis, ataxicsclerosis, progressive systemic sclerosis, scleritis, sclerodermia,multiple sclerosis, sclerosis disseminata, acquired spenic atrophy,infertility due to antispermatozoan antibodies, thrombocytopenia,idiopathic thrombocytopenia purpura, thymoma, acute anterior uveitis,vitiligo, AIDS, HIV, SCID and Epstein Barr virus associated diseasessuch as Sjorgren's syndrome, virus (AIDS or EBV) associated B celllymphoma, parasitic diseases such as Leishmania, and immunosuppresseddisease states such as viral infections following allografttransplantations, AIDS, cancer, chronic active hepatitis diabetes, toxicshock syndrome and food poisoning.

Furthermore, the invention relates to a method of treatment orprevention of diseases which comprises the administration of aneffective amount of compounds of the formula (I) or a pharmaceuticallyacceptable salt or physiologically functional derivative or astereoisomer thereof.

In a preferred embodiment, the invention relates to the use of compoundsof the formula (I) or a pharmaceutically acceptable salt orphysiologically functional derivative or a stereoisomer thereof ifdesired with appropriate adjuvants and additives for the production of amedicament for the treatment or prevention of skin diseases in which Tcells play a role; especially preferably the skin diseases are selectedfrom the group consisting of psoriasis, atopic dermatitis, alopeciaareata, alopecia totalis, alopecia subtotalis, alopecia universalis,alopecia diffusa, lupus erythematodes of the skin, lichen planus,dermatomyostis of the skin, atopic eczema, morphea, sklerodermia,psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasisinversa, alopecia areata ophiasis-type, androgenetic alopecia, allergiccontact eczema, irritative contact eczema, contact eczema, pemphigusvulgaris, pemphigus foliaceus, pemphigus vegetans, scarring mucosalpemphigoid, bullous pemphgoid, mucous pemphigoid, dermatitis, dermatitisherpetiformis duhring, urticaria, necrobiosis lipoidica, erythemanodosum, lichen vidal, prurigo simplex, prurigo nodularis, prurigoacuta, linear IgA dermatosis, polymorphic light dermatoses, erythemasolaris, lichen sclerosus et atrophicans, exanthema of the skin, drugexanthema, purpura chronica progressiva, dihidrotic eczema, Eczema,fixed drug exanthema, photoallergic skin reaction, lichen simplexeriorale, dermatitis and “Graft versus Host-Disease”, acne, rosacea,scarring, keloids and vitiligo.

Moreover, the compounds of the present invention can be used for thetreatment of diseases resulting from ischemia and/or reperfusion injuryof organs and/or of parts of the body selected from the group comprisingheart, brain, peripheral limb, kidney, liver, spleen and lung, and/orwherein the endothelial dysfunction is associated with diseases selectedfrom a group comprising infarctions such as myocardial infarction andcritical limb ischemia, and/or wherein the endothelial dysfunction isassociated with diseases selected from the group comprising ischemicdiseases such as peripheral arterial occlusive disease, e.g. criticalleg ischemia, myocardial infarction and ischemic diseases of organs,e.g. of the kidney, spleen, brain and lung.

The compounds of this invention also can be applied for the preventionand the treatment of neurological diseases or disorders (diseases ordisorders associated with the brain and nervous system), including butnot limited to, Alzheimer's disease, Parkinson's disease,Creutzfeld-Jacob Disease, Lewy Body Dementia, amyotrophic lateralsclerosis, stroke, epilepsy, multiple sclerosis, myasthenia gravis,Huntington's Disease, Down's Syndrome, nerve deafness, and Meniere'sdisease.). Other neurological diseases and disorders will be apparent tothose of skill in the art and are encompassed by the definition as usedin this invention.

The compounds of the present invention can further be used for diseasesthat are caused by protozoal infestations in humans and animals. Suchveterinary and human pathogenic protozoas are preferably intracellularactive parasites of the phylum Apicomplexa or Sarcomastigophora,especially Trypanosoma, Plasmodia, Leishmania, Babesia and Theileria,Cryptosporidia, Sacrocystida, Amoebia, Coccidia and Trichomonadia. Theseactive substances or corresponding drugs are especially suitable for thetreatment of Malaria tropica, caused by Plasmodium falciparum, Malariatertiana, caused by Plasmodium vivax or Plasmodium ovale and for thetreatment of Malaria quartana, caused by Plasmodium malariae. They arealso suitable for the treatment of Toxoplasmosis, caused by Toxoplasmagondii, Coccidiosis, caused for instance by Isospora belli, intestinalSarcosporidiosis, caused by Sarcocystis suihominis, dysentery caused byEntamoeba histolytica, Cryptosporidiosis, caused by Cryptosporidiumparvum, Chargas' disease, caused by Trypanosoma cruzi, sleepingsickness, caused by Trypanosoma brucei rhodesiense or gambiense, thecutaneous and visceral as well as other forms of Leishmaniosis. They arealso suitable for the treatment of animals infected by veterinarypathogenic protozoa, like Theileria parva, the pathogen causing bovineEast coast fever, Trypanosoma congolense congolense or Trypanosoma vivaxvivax, Trypanosoma brucei brucei, pathogens causing Nagana cattledisease in Africa, Trypanosoma brucei evansi causing Surra, Babesiabigemina, the pathogen causing Texas fever in cattle and buffaloes,Babesia bovis, the pathogen causing European bovine Babesiosis as wellas Babesiosis in dogs, cats and sheep, Sarcocystis ovicanis and ovifelispathogens causing Sarcocystiosis in sheep, cattle and pigs,Cryptosporidia, pathogens causing Cryptosporidioses in cattle and birds,Eimeria and Isospora species, pathogens causing Coccidiosis in rabbits,cattle, sheep, goats, pigs and birds, especially in chickens andturkeys. The use of the compounds of the present invention is preferredin particular for the treatment of Coccidiosis or Malaria infections, orfor the preparation of a drug or feed stuff for the treatment of thesediseases. This treatment can be prophylactic or curative. In thetreatment of malaria, the compounds of the present invention may becombined with other anti-malaria agents.

The compounds of the present invention can further be used for theprophylaxis and/or treatment of infectious diseases caused among othersby bacteria and viruses, including opportunistic infections in a mammal,including a human. Said method comprises administering to the mammal anamount of at least one compound of the general formula (I) and/orpharmaceutically acceptable salts thereof, effective to prevent and/ortreat said infectious disease and/or opportunistic infection.

The infectious disease can be selected from the group comprising AIDS,Alveolar Hydatid Disease (AHD, Echinococcosis), Amebiasis (Entamoebahistolytica Infection), Angiostrongylus Infection, Anisakiasis, Anthrax,Babesiosis (Babesia Infection), Balantidium Infection (Balantidiasis),Baylisascaris Infection (Raccoon Roundworm), Bilharzia(Schistosomiasis), Blastocystis hominis Infection (Blastomycosis),Boreliosis, Botulism, Brainerd Diarrhea, Brucellosis, BSE (BovineSpongiform Encephalopathy), Candidiasis, Capillariasis (CapillariaInfection), CFS (Chronic Fatigue Syndrome), Chagas Disease (AmericanTrypanosomiasis), Chickenpox (Varicella-Zoster virus), Chlamydiapneumoniae Infection, Cholera, Chronic Fatigue Syndrome, CJD(Creutzfeldt-Jakob Disease), Clonorchiasis (Clonorchis Infection), CLM(Cutaneous Larva Migrans, Hookworm Infection), Coccidioidomycosis,Conjunctivitis, Coxsackievirus A16 (Hand, Foot and Mouth Disease),Cryptococcosis, Cryptosporidium Infection (Cryptosporidiosis), Culexmosquito (Vector of West Nile Virus), Cutaneous Larva Migrans (CLM),Cyclosporiasis (Cyclospora Infection), Cysticercosis(Neurocysticercosis), Cytomegalovirus Infection (CMV), Dengue/DengueFever, Dipylidium Infection (Dog and Cat Flea Tapeworm), Ebola VirusHemorrhagic Fever, Echinococcosis (Alveolar Hydatid Disease),Encephalitis, Entomoeba coli Infection, Entomoeba dispar Infection,Entomoeba hartmanni Infection, Entomoeba histolytica Infection(Amebiasis), Entomoeba polecki Infection, Enterobiasis (PinwormInfection), Enterovirus Infection (Non-Polio), Epstein-Barr VirusInfection, Escherichia coli Infection, Foodborne Infection, Foot andmouth Disease, Fungal Dermatitis, Gastroenteritis, Group A streptococcalDisease, Group B streptococcal Disease, diseases caused bystaphylococcal infections (Staphylococcus aureus and otherstaphylococcus species), diseases caused by infections with pseudomonasaeruginosa and other pseudomonas species, Burkholderia cepaciainfections, Hansen's Disease (Leprosy), Hantavirus Pulmonary Syndrome,Head Lice Infestation (Pediculosis), Helicobacter pylori Infection,Hematologic Disease, Hendra Virus Infection, Hepatitis, Herpes Zoster(Shingles), HIV Infection, Human Ehrlichiosis, Human Parainfluenza VirusInfection, Influenza, Isosporiasis (Isospora Infection), Lassa Fever,Leishmaniasis, Kala-azar (Kala-azar, Leishmania Infection), Leprosy,Lice (Body lice, Head lice, Pubic lice), Lyme Disease, MarburgHemorrhagic Fever, Measles, Meningitis, Mosquito-borne Diseases,Mycobacterium avium Complex (MAC) Infection, Naegleria Infection,Nosocomial Infections, Nonpathogenic Intestinal Amebae Infection,Onchocerciasis (River Blindness), Opisthorciasis (OpisthorcisInfection), Parvovirus Infection, Plague, PCP (Pneumocystis cariniiPneumonia), Polio, Q Fever, Rabies, Respiratory Syncytial Virus (RSV)Infection, Rheumatic Fever, Rift Valley Fever, River Blindness(Onchocerciasis), Rotavirus Infection, Roundworms Infection,Salmonellosis, Salmonella Enteritidis, Scabies, Shigellosis, Shingles,Sleeping Sickness, Smallpox, Streptococcal Infection, Tapeworm Infection(Taenia Infection), Tetanus, Toxic Shock Syndrome, Tuberculosis, Ulcers(Peptic Ulcer Disease), Valley Fever, Vibrio parahaemolyticus Infection,Vibrio vulnificus Infection, Viral Hemorrhagic Fever, Warts, Waterborneinfectious Diseases, West Nile Virus Infection (West Nile Encephalitis),Whooping Cough, Yellow Fever.

The compounds of formula (I), (II) or (III) and their pharmacologicallyacceptable salts can be administered to animals, preferably to mammals,and in particular to humans, dogs and chickens as therapeutics per se,as mixtures with one another or in the form of pharmaceuticalpreparations which allow enteral or parenteral use and which as activeconstituent contain an effective dose of at least one compound of theformula (I), (II) or (III) or a salt thereof, in addition to customarypharmaceutically innocuous excipients and additives. The compounds offormula (I), (II) or (III) can also be administered in form of theirsalts, which are obtainable by reacting the respective compounds withphysiologically acceptable acids and bases.

The production of medicaments containing the compounds of formula (I),(II) or (III) according to the invention and their application can beperformed according to well-known pharmaceutical methods.

While the compounds of formula (I), (II) or (III) according to theinvention for use in therapy may be administered in the form of the rawchemical compound, it is preferred to introduce the active ingredient,optionally in the form of a physiologically acceptable salt in apharmaceutical composition together with one or more adjuvants,excipients, carriers, buffers, diluents, and/or other customarypharmaceutical auxiliaries. Such salts of the compounds may be anhydrousor solvated.

In a preferred embodiment, the invention provides medicaments comprisingcompounds of formula (I), (II) or (III) according to the invention, or apharmaceutically acceptable salt or physiologically functionalderivative or a stereoisomer thereof, together with one or morepharmaceutically acceptable carriers thereof, and, optionally, othertherapeutic and/or prophylactic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not harmful to the recipient thereof.

A medicament of the invention may be those suitable for oral, rectal,bronchial, nasal, topical, buccal, sub-lingual, transdermal, vaginal orparenteral (including cutaneous, subcutaneous, intramuscular,intraperitoneal, intravenous, intraarterial, intracerebral, intraocularinjection or infusion) administration, or those in a form suitable foradministration by inhalation or insufflation, including powders andliquid aerosol administration, or by sustained release systems. Suitableexamples of sustained release systems include semipermeable matrices ofsolid hydrophobic polymers containing the compound of the invention,which matrices may be in form of shaped articles, e.g. films ormicrocapsules.

The compounds according to the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofmedicament and unit dosages thereof. Such forms include solids, and inparticular tablets, filled capsules, powder and pellet forms, andliquids, in particular aqueous or non-aqueous solutions, suspensions,emulsions, elixirs, and capsules filled with the same, all for oral use,suppositories for rectal administration, and sterile injectablesolutions for parenteral use. Such Medicament and unit dosage formsthereof may comprise conventional ingredients in conventionalproportions, with or without additional active compounds or principles,and such unit dosage forms may contain any suitable effective amount ofthe active ingredient commensurate with the intended daily dosage rangeto be employed.

The compound useable according to the invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a compound of formula (I), (II) or (III)according to the invention or a pharmaceutically acceptable salt orstereosomer thereof.

For preparing a medicament from a compounds of formula (I), (II), or(III) pharmaceutically acceptable carriers can be either solid orliquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier can be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “preparation” is intended to include theformulation of the active compound with encapsulating material ascarrier providing a capsule in which the active component, with orwithout carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify. Compositions suitable for vaginaladministration may be presented as pessaries, tampons, creams, gels,pastes, foams or sprays containing in addition to the active ingredientsuch carriers as are known in the art to be appropriate. Liquidpreparations include solutions, suspensions, and emulsions, for example,water or water-propylene glycol solutions. For example, parenteralinjection liquid preparations can be formulated as solutions in aqueouspolyethylene glycol solution.

The compounds of formula (I), (II), or (III) according to the presentinvention may thus be formulated for parenteral administration (e.g. byinjection, for example bolus injection or continuous infusion) and maybe presented in unit dose form in ampoules, pre-filled syringes, smallvolume infusion or in multi-dose containers with an added preservative.The compositions may take such forms as suspensions, solutions, oremulsions in oily or aqueous vehicles, and may contain formulationagents such as suspending, stabilising and/or dispersing agents.Alternatively, the active ingredient may be in powder form, obtained byaseptic isolation of sterile solid or by lyophilization from solution,for constitution with a suitable vehicle, e.g. sterile, pyrogen-freewater, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

In one embodiment of the present invention, the medicament is appliedtopically or systemically or via a combination of the two routes.

In an especially preferred embodiment of the present invention themedicament is applied topically. This reduces possible side effects andlimits the necessary treatment to those areas affected.

Preferably the medicament is prepared in form of an ointment, a gel, aplaster, an emulsion, a lotion, a foam, a cream of a mixed phase oramphiphilic emulsion system (oil/water-water/oil mixed phase), aliposome, a transfersome, a paste or a powder.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilisingagents, dispersing agents, suspending agents, thickening agents, orcolouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form. Tablets or capsules for oral administration andliquids for intravenous administration and continuous infusion arepreferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co. Easton, Pa.).

Pharmaceutical compositions can also contain two or more compounds ofthe formula (I), (II) or (III) or their pharmacologically acceptablesalts and also other therapeutically active substances.

Thus, the compounds of the present invention can be used in the form ofone compound alone or in combination with other active compounds—forexample with medicaments already known for the treatment of theaforementioned diseases, whereby in the latter case a favorableadditive, amplifying effect is noticed. Suitable amounts to beadministered to humans may range from 5 to 500 mg.

To prepare the pharmaceutical preparations, pharmaceutically inertinorganic or organic excipients can be used. To prepare pills, tablets,coated tablets and hard gelatin capsules, for example, lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts, etc. canbe used. Excipients for soft gelatin capsules and suppositories are, forexample, fats, waxes, semi-solid and liquid polyols, natural or hardenedoils etc. Suitable excipients for the production of solutions and syrupsare, for example, water, sucrose, invert sugar, glucose, polyols etc.Suitable excipients for the production of injection solutions are, forexample, water, alcohols, glycerol, polyols or vegetable oils.

The dose can vary within wide limits and is to be suited to theindividual conditions in each individual case. For the above uses theappropriate dosage will vary depending on the mode of administration,the particular condition to be treated and the effect desired. Ingeneral, however, satisfactory results are achieved at dosage rates ofabout 1 to 100 mg/kg animal body weight preferably 1 to 50 mg/kg. Ingeneral, suitable dosage rates for larger mammals, for example humans,may be of the order of from about 10 mg to 3 g/day, convenientlyadministered once, in divided doses 2 to 4 times a day, or in sustainedrelease form.

In general, a daily dose of approximately 10 mg to 5000 mg, preferably50 to 500 mg, per human individual is appropriate in the case of theoral administration. In the case of other administration forms too, thedaily dose is in similar ranges. For topical delivery, depending on thepermeability of the skin, the type and the severity of the disease anddependent on the type of formulation and frequency of application,different concentrations of active compounds within the medicament canbe sufficient to elicit a therapeutic effect by topical application.Preferably the concentration of an active compound or a pharmaceuticallyacceptable salt thereof or a physiologically functional derivative or astereoisomer thereof within a medicament according to the invention isin the range of between 1 μmol/l and 100 mmol/l.

The following examples and figures are included to demonstrate preferredembodiments of the invention. It should be appreciated by those of skillin the art that the techniques disclosed in the examples that followrepresent techniques discovered by the inventors to function well in thepractice of the invention, and thus can be considered preferred modesfor its practice. However, those of skill in the art should, in light ofthe present disclosure, appreciate that many changes can be made in thespecific embodiments that are disclosed without departing from thespirit and scope of the invention as set out in the appended claims. Allreferences cited are incorporated herein by reference.

EXAMPLES

Abbreviations: min, minute(s); h, hour(s); r.t., room temperature; t-,tert-.

NMR spectra: Bruker Avance 300 MHz. The spectra were recorded at 300 MHz(¹H-NMR), respectively, using the residual solvent peak as an internalstandard (DMSO-d₆, δ_(H)=2.49; CD₃OD, δ_(H)=3.31; CDCl₃, δ_(H)=7.26;CD₃CN, δ_(H)=1.93; (CD₃)₂CO, δ_(H)=2.05).

Analytical LC/ESI-MS: 2× Waters 600 Multisolvent Delivery System. 50 μlsample loop. Column, Chromolith Speed ROD RP18e (Merck, Darmstadt),50×4.6 mm, with 2 μm prefilter (Merck). Eluent A, H₂O+0.1% HCO₂H; eluentB, MeCN. Gradient, 5% B to 100% B within 5 min; flow, 3 ml/min. WatersLCZ single quadrupol mass spectrometer with electrospray source. MSmethod, MS8minPM-80-800-20V; positive/negative ion mode scanning, m/z80-800 in 1 s; capillary, 3.5 kV; cone voltage, 20 V; multipliervoltage, 400 V; probe and desolvation gas temperature, 120° C. and 350°C., respectively. Waters 2487 Dual λAbsorbance Detector, set to 254 nm.

Preparative HPLC-MS: Waters 600 Multisolvent Delivery System withpeparative pump heads. 2000 μl or 5000 μl sample loop. Column, WatersX-Terra RP18, 7 μm, 19×150 mm with X-Terra RP18 guard cartridge 7 μm,19×10 mm; used at flow rate 20 ml/min or YMC ODS-A, 120 Å, 40×150 mmwith X-Terra RP18 guard cartridge 7 μm, 19×10 mm; used at flow rate 50ml/min. Make-up solvent: MeCN—H₂O—HCO₂H 80:20:0.05 (v:v:v). Eluent A,H₂O+0.1% HCO₂H; eluent B, MeCN. Different linear gradients from 5-100%eluent B, adapted to sample. Injection volume: 500 μl-2000 μl dependingon sample. Waters ZQ single quadrupol mass spectrometer withelectrospray source. Positive or negative ion mode scanning m/z 80-800in 1 s; capillary, 3.5 kV or 3.0 kV; cone voltage, 20 V; multipliervoltage, 400 V; probe and desolvation gas temperature, 120° C. and 350°C., respectively. Waters Fraction Collector II with mass-triggeredfraction collection. Waters 996 photo diode array detector.

Synthesis of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acidt-butyl ester

Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8mmol) was dissolved under inert conditions in 35 ml dryN,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) andtriethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture wascooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimidhydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutesand the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for18 h.

The solvent was removed under vacuum and the residue was suspended in400 ml ethylacetate. The organic layer was extracted 3 times with 100 mlof 1 M citric acid, aqueous sodium carbonate and twice with 100 mlbrine, dried over MgSO₄ and filtered. The solvent was removed and theresidue was purified by distillation resulting in a yield of 80%.

Synthesis of 4-Formyl-piperidine-1-carboxylic acid t-butyl ester

4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butylester (1.0 eq, 16.4 mmol) was dissolved in 100 ml dry tetrahydrofuraneunder inert atmosphere. This solution was added dropwise over a periodof 1 h to a suspension of lithiumalanate (3.0 eq, 49.6 mmol) in 70 mldry tetrahydrofurane at −50° C. During the adding of the mixture, thetemperature was held at −50° C. and then allowed to warm to 0° C. within3 h. The mixture was cooled to −78° C. and quenched carefully with 100ml 1 M citric acid. The mixture was warmed up to r.t. and diluted with400 ml ethylacetate. The phases were separated and the aqueous phase wasextracted 3 times with 70 ml ethylacetate. The combined organic layerswere extracted 3 times with 100 ml 1 M citric acid, aqueous sodiumcarbonate and 2 times with 100 ml brine, dried over MgSO₄ and filtrated.The solvent was removed and the residue was purified by distillationresulting in a yield of 85%

Synthesis of4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-1-carboxylicacid t-butyl ester

4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol)was dissolved under inert conditions in 40 ml toluene. To this solutionL-cystein ethylester hydrochloride (1.6 eq, 21 mmol) and triethylamine(1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. Thegenerated water was removed with a Dean & Stark trap.

The solvent was removed and the residue was dissolved in 100 mlethylacetate. The organic layer was extracted 3 times with 50 ml 1 Mcitric acid, aqueous potassium hydrogen carbonate and 2 times with 50 mlbrine, dried over MgSO₄ and filtrated. The solvent was removed and theresidue was purified by silica gel chromatography using a PE/EA 4:1gradient. Yield: 75%

Synthesis of 4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-1-carboxylicacid t-butyl ester

4-(4-Ethoxycarbonyl-4,5-dihydro-thiazol-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (1.0 eq, 8.7 mmol) was solved in 160 ml tolueneunder inert conditions. To this solution MnO₂ (15.0 eq, 130 mmol) wasadded. The reaction was heated to 70° C. under stirring for 5 h. Themixture was filtered over celite and the filtration agent was washed 3times with 30 ml toluene and ethylacetate. The combined organic layerswere distilled in vacuo. The residue was purified by silica gelchromatography using a DCM/MeOH 95:5 gradient. Yield: 30%

C-Terminal Functionalisation

4-(4-Ethoxycarbonyl-thiazol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (1.0 eq, 2.9 mmol) was dissolved under inert gas in 40ml dioxane. Under stirring 1.5 ml aqueous 2 N NaOH was added dropwiseover a period of 10 min. Afterwards the mixture was stirred for 2 h atr.t.

The reaction was neutralized with 2 N HCl and the solvent was evaporatedin vacuo. The residue was dissolved in 50 ml ethylacetate. The organiclayer was extracted 3 times with 10 ml of 1 M citric acid and water,dried over MgSO₄ and filtered. The solvent was removed and the residuewas dried in vacuo. Yield 95%

4-(4-Carboxy-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester(1 eq) was dissolved under inert conditions in dry dimethylacetamide(0.03 mmol/ml). To this solution aryl- or alkylamine (1 eq),diisopropylethylamine (2 eq) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2eq) was added. The reaction mixture was stirred for 12 h at r.t.

The solvent was removed in vacuo and the residue was dissolved inethylacetate. The organic layer was extracted 3 times with 1 M citricacid, aqueous potassium hydrogen carbonate and 2 times with brine, driedover MgSO₄ and filtered. The solvent was removed and the residue waspurified by silica gel chromatography using a DCM/MeOH 95:5 gradient.Yield: 40-80%

N-Terminal Functionalisation

The N-protected substrate was treated under inert condition with 4 MHCl/dioxane (conc. 0.03 mmol substrate in 1 mL HCl/dioxane) and wasstirred for 2 h at r.t.

The solvent was removed in vacuo to yield the HCl salt of the free aminewithout further purification.

The free amino compound (1 eq) was dissolved under inert conditions indry dimethylacetamide (0.03 mmol/ml). To this solution aryl- oralkylcarboxylic acid (1 eq), diisopropylethylamine (2 eq) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2eq) was added in this sequence and the reaction mixture was stirred for12 h at r.t.

The solvent was removed in vacuo and the residue was dissolved inethylacetate. The organic layer was extracted 3 times with 1 M citricacid, aqueous potassium hydrogen carbonate and 2 times with brine, driedover MgSO₄ and filtered. The solvent was removed and the residue waspurified by silica gel chromatography using a DCM/MeOH 95:5 gradient.Yield: 40-80%

General Synthesis for Compounds of Type (III) and (II)

Procedure for the Synthesis of Compounds of Type (IIIa), (IIIc), (IIa)and (IIb)

7.3×10⁻⁴ mol of the benzoic acid derivative (VI) was dissolved in 5 mlDMF and 1 eq. of Hünig's base was added, stirring the reaction mixturefor a few minutes, followed by the addition of 1 eq. of HBTU and furtherstirring at r.t. for 2 min. Afterwards 1 eq.2-Amino-thiazole-4-carboxylic acid ethyl ester was added, stirring themixture overnight at the same temperature. Subsequently, the solvent wasremoved by filtration and the residue redissolved in 5 ml dioxane andtreated with 0.5 ml of a 1M NaOH solution. After the reaction wascomplete, the pH was decreased to 1-2 with a 1M HCl solution and theprecipitated product (VII) filtered and dried in vacuo. For the nextstep, intermediate (VII) was dissolved in 3 ml DMF and 1 eq. of Hünig'sbase was added, stirring the reaction mixture for a few minutes,followed by the addition of 1 eq. of HBTU and further stirring at r.t.for 2 min. Afterwards 1 eq. the amino component was added, stirring themixture overnight at the same temperature. Subsequently, the solvent wasremoved by filtration and the crude product redissolved in 10 ml ethylacetate, washed twice with 10 ml citric acid (1M solution), 10 ml sat.NaHCO₃ solution and 10 ml water. The organic phase was then evaporatedand the residue dried over MgSO₄. The solvent was removed and finalpurification was realised by preparative HPLC as described above.

As a second variant for the first step, the corresponding acid chloridederivative of (VI) could be reacted with the2-Amino-thiazole-4-carboxylic acid ethyl ester (1:1) using 1.1 eq. ofHünig's base.

Procedure for the Synthesis of Compounds of Type (IIIb, d, e, f) and(IIc, d)

6.3×10⁻⁴ mol of 2-Bromo-thiazole-4-carboxylic acid ethyl ester (X) wasdissolved in 10 ml THF together with 2.2 eq. of the respectivepiperazine (IX), allowing to reflux overnight. Afterwards the solventwas removed in vacuo and the residue purified by pTLC (PE/EE 2/1).

The second and the third step of the reaction were accomplished asdescribed above under the procedure for the synthesis of compounds oftype (IIIa) and (IIIc).

For as synthesis-protocol of type (IIIb, d, e, f and IIc, d) compoundswith Z═CH, see WO 2004/058750.

Exemplary compounds of formula (I) of the present invention include, butare not limited to, the followings:

LC/(+)- Cp. Name Mass ESI-MS: ¹H-NMR 1 [4-(1H-Indol-3-yl)-piperidin- 501502 [M + H]⁺ δ = 1.69-2.04 (m, 4H, 2 CH₂), 1-yl]-{2-[1-(pyrazine-2-2.07-2.24 (m, 4H, 2 CH₂), carbonyl)-piperidin-4-yl]- 2.96-3.4 (m, 6H, 2CH₂, 2 CH), thiazol-4-yl}-methanone 4.05-4.91 (m, 4H, 2 CH₂), 6.99-7.78(m, 6H, CH_(Ar)), 8.01 (s, 1H, NH), 8.5-8.9 (m, 3H, CH_(Ar)). 24-[5-(4-{4-[4-(1H-Indol-3-yl)- 621 622 [M + H]⁺ piperidine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)- 5-oxo-pentyl]-tetrahydro-thieno[3,4-d]imidazol-2-one 3 4-[4-(4-Benzhydryl- 547 548 [M + H]⁺piperazine-1-carbonyl)- thiazol-2-yl]-piperidine-1- carboxylic acidtert-butyl ester 4 2-Phenyl-1-(4-{4-[4-(3- 543 544 [M + H]⁺ δ =1.48-1.69 (m, 2H, CH₂), trifluoromethyl-phenyl)- 2.02-2.13 (m, 2H, CH₂),piperazine-1-carbonyl]- 2.70-2.9 (m, 2H, CH₂),thiazol-2-yl}-piperidin-1-yl)- 3.22-3.38 (m, 5H, 2 CH₂), 1 CH), 3.74 (s,ethanone 2H, CH₂), 4.51-4.60 (m, 2H, 1 CH₂), 7.06-7.91 (m, 10H CH_(Ar)).5 3-[2-(4-{4-[4-(1H-Indol-3-yl)- 597 598 [M + H]⁺piperidine-1-carbonyl]- thiazol-2-yl}-piperidin-1-yl)-2-oxo-ethyl]-5-methoxy- indan-1-one 6 2-(4-Fluoro-phenyl)-1-(4-{4- 561562 [M + H]⁺ δ = 1.58-1.7 (m, 2H, CH₂), [4-(3-trifluoromethyl-phenyl)-2.06-2.18 (m, 2H, CH₂), piperazine-1-carbonyl]- 2.75 (s, 2H, CH₂)2.78-2.9 (m, 2H, thiazol-2-yl}-piperidin-1-yl)- CH₂), 3.27-3.38 (m, 5H,2 ethanone CH₂, 1 CH), 4.5-4.61 (m, 2H, CH₂), 7.02-7.94 (m, 9H CH_(Ar)).7 2,2-Diphenyl-1-(4-{4-[4-(3- 619 620 [M + H]⁺ δ = 1.3-1.75 (m, 2H, CH₂)trifluoromethyl-phenyl)- 1.94-2.19 (m, 2H, CH₂), piperazine-1-carbonyl]-2.9-3.02 (m, 2H, CH₂) thiazol-2-yl}-piperidin-1-yl)- 3.18-3.43 (m, 6H, 2CH, 2 CH₂) ethanone 4.18-4.7 (m, 2H, CH₂), 7.11-7.95 (m, 15H, CH_(Ar)).8 1-(4-{4-[4-(1H-Indol-3-yl)- 603 604 [M + H]⁺ piperidine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)- 3,3-diphenyl-propan-1-one 94-{4-[4-(3-Trifluoromethyl- 525 526 [M + H]⁺ δ = 1.45 (s, 9H, 3 CH₃),phenyl)-piperazine-1- 1.65-1.78 (m, 2H, CH₂), carbonyl]-thiazol-2-yl}-2.05-2.18 (m, 2H, CH₂), 2.91-3.03 (m, 2H, piperidine-1-carboxylic acidCH₂), 3.29 (m_(c), 1H, CH), tert-butyl ester 3.38 (m_(c), 1H, 2 CH₂)4.10-4.19 (m, 2H, CH₂), 7.10-7.96 (m, 5H, CH_(Ar)) 10(2-Piperidin-4-yl-thiazol-4- 424 425 [M + H]⁺ yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 11 {2-[1-(4,7-Dimethyl- 569 570 [M +H]⁺ δ = 1.75-2.07 (m, 4H, 2 CH₂), pyrazolo[5,1-c][1,2,4]triazine-2.08-2.42 (m, 4H, 2 CH₂), 3-carbonyl)-piperidin-4-yl]- 2.63 (s, 3H,CH₃), 2.87 (s, 3H, thiazol-4-yl}-[4-(1H-indol-3- CH₃), 2.94-3.4 (m, 6H,2 CH₂), yl)-piperidin-1-yl]-methanone 2 CH), 3.83 (m_(C,) 1H, CH₂),4.44-4.6 (m, 1H, CH₂) 4.84 (m_(c,) 2H, CH₂), 6.98-7.79 (m, 7H, CH_(Ar)),8.02 (s, 1H, NH). 12 1-(4-{4-[4-(1H-Indol-3-yl)- 513 514 [M + H]⁺ δ =1.65-1.93 (m, 4H, 2 CH₂), piperidine-1-carbonyl]- 1.96-2.24 (m, 4H, 2CH₂), thiazol-2-yl}-piperidin-1-yl)- 2.77-2.91 (m, 2H, CH₂),2-phenyl-ethanone 2.93-3.05 (m, 1H, CH₂), 3.07-3.2 (m, 2H, 2 CH)3.25-3.34 (m, 1H, CH₂), 3.76 (s, 2H, CH₂), 3.94 (m_(c,) 1H, CH₂),4.43-4.57 (m, 1H, CH₂), 4.66 (m_(c,) 1H, CH₂), 4.75-4.90 (m, 1H, CH₂),6.98-7.75 (m, 11H, CH_(Ar)), 7.98 (s, 1H, NH). 135-Methoxy-3-[2-oxo-2-(4-{4- 627 628 [M + H]⁺[4-(3-trifluoromethyl-phenyl)- piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)- ethyl]-indan-1-one 141-(4-Fluoro-phenyl)-2-(4-{4- 531 532 [M + H]⁺ δ = 1.58-1.85 (m, 4H, 2CH₂), [4-(1H-indol-3-yl)-piperidine- 2.07-2.19 (m, 4H, 2 CH₂),1-carbonyl]-thiazol-2-yl}- 2.64-3.64 (m, 6H, 2 CH₂, 2piperidin-1-yl)-ethanone CH), 3.97 (m_(C,) 1H, CH₂), 4.41 (m_(C,) 2H,CH₂) 4.49-4.7 (m, 1H, CH₂) 5.48 (s, 2H, CH₂), 6.84-7.71 (m, 10HCH_(Ar)). 15 3-Phenyl-1-(4-{4-[4-(3- 553 554 [M + H]⁺ δ = 1.71-1.97 (m2H, CH₂), trifluoromethyl-phenyl)- 2.20-2.35 (m, 2H, CH₂),piperazine-1-carbonyl]- 3.02 (m_(c,) 1H, CH) 3.42-3.55 (m, 6H,thiazol-2-yl}-piperidin-1-yl)- 2 CH₂), 4.51-4.61 (m, 2H, propynone CH₂),7.2-8.0 (m, 9H, CH_(Ar)). 16 3,3-Diphenyl-1-(4-{4-[4-(3- 633 634 [M +H]⁺ δ = 1.44-1.59 (m, 2H, CH₂) trifluoromethyl-phenyl)- 2.04-2.12 (m,2H, CH₂), piperazine-1-carbonyl]- 2.7-2.83 (m, 2H, CH₂),thiazol-2-yl}-piperidin-1-yl)- 3.08-3.34 (m, 4H, 2 CH, CH₂),propan-1-one 3.34-3.41 (m, 4H, 2 CH₂), 4.46-463 (m, 2H, CH₂), 7.11-7.95(m, 15H, CH_(Ar)). 17 {2-[1-(Pyrazine-2-carbonyl)- 531 532 [M + H]⁺ δ =1.83-1.99 (m, 2H, CH₂), piperidin-4-yl]-thiazol-4-yl}- 2.07-2.35 (m, 2H,CH₂), [4-(3-trifluoromethyl-phenyl)- 2.73-2.95 (m, 2H, CH₂), 3.13(m_(c,) 1H, piperazin-1-yl]-methanone CH), 3.33-3.44 (m, 4H, 2 CH₂),4.6-4.74 (m, 2H, CH₂), 7.11-8.88 (m, 8H, CH_(Ar)). 18{2-[1-(4,7-Dimethyl- 599 600 [M + H]⁺ pyrazolo[5,1-c][1,2,4]triazine-3-carbonyl)-piperidin-4-yl]- thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone 194-(4-{2-[4-(1H-Indol-3-yl)- 495 496 [M + H]⁺ δ = 1.46 (s 9H 3 CH₃),piperidin-1-carbonyl]}- 1.67-1.92 (m, 4H, 2 CH₂),thiazol-2-yl)-piperidine-1- 2.06-2.23 (m, 4H, 2 CH₂), carboxylic acidtert-butyl ester 2.84-2.95 (m, 2H, 1 CH₂), 2.97-3.08 (m, 1H, 1 CH₂),3.1-3.22 (m, 2H, 2CH) 3.23-3.36 (m, 1H, 1 CH₂), 4.11-4.23 (m, 2H, 1CH₂), 4.5-4.91 (m, 2H 1 CH₂), 6.96-7.77 (m, 6H CH_(Ar)), 7.98 (s 1H,NH). 20 1-{4-[4-(4-Benzhydryl- 583 584 [M + H]⁺ piperazine-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}- 2-(4-fluoro-phenyl)-ethanone 21(4-Benzhydryl-piperazin-1- 621 622 [M + H]⁺ yl)-{2-[1-(4,7-dimethyl-pyrazolo[5,1-c][1,2,4]triazine- 3-carbonyl)-piperidin-4-yl]-thiazol-4-yl}-methanone 22 (4-Benzhydryl-piperazin-1- 447 448 [M + H]⁺yl)-(2-piperidin-4-yl-thiazol-4- yl)-methanone 23 1-{4-[4-(4-Benzhydryl-565 566 [M + H]⁺ δ = 1.35 (m_(C,) 1H, CH₂), piperazine-1-carbonyl)- 1.60(m_(C,) 1H, CH₂), 1.93 (m_(C,) 2H, thiazol-2-yl]-piperidin-1-yl}- CH₂),2.37 (m_(C,) 4H, 2 CH₂), 2-phenyl-ethanone 2.71 (m_(C,) 1H, CH₂),2.97-3.12 (m, 2H, CH₂, CH), 3.67 (s, 2H, CH₂), 3.69-3.91 (m, 5H, 6 CH₂),4.18 (s, 1H, CH), 4.58 (m_(C,) 1H, CH₂), 7.09-7.68 (m, 16H, CH_(Ar)). 243-(2-{4-[4-(4-Benzhydryl- 649 650 [M + H]⁺ piperazine-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}- 2-oxo-ethyl)-5-methoxy- indan-1-one

Exemplary compounds of formula (I), (II) and (III) of the presentinvention include, but are not limited to, the followings:

LC/(+)-ESI- Biological Cp. Name Mass MS: activity¹⁾ 12-Morpholin-4-yl-thiazole-4-carboxylic 357 358 [M + H]⁺ + acid(5,6-dimethyl-1H-benzoimidazol-2- yl)-amide 22-[3-(2-Trifluoromethoxy-phenyl)-ureido]- 462 463 [M + H]⁺ +thiazole-4-carboxylic acid (1H- benzoimidazol-2-yl)-amide 3N-{4-[4-(4-Fluoro-phenyl)-piperazine-1- 494 495 [M + H]⁺ ++carbonyl]-thiazol-2-yl}-2-trifluoromethoxy- benzamide 42-(2-Fluoro-benzoylamino)-thiazole-4- 409 410 [M + H]⁺ + carboxylic acid(5,6-dimethyl-1H- benzoimidazol-2-yl)-amide 5N-[5-(4-Pyrimidin-2-yl-piperazine-1- 478 479 [M + H]⁺ +carbonyl)-thiazol-2-yl]-2-trifluoromethoxy- benzamide 6N-{4-[N′-(1H-Benzoimidazol-2-yl)- 441 442 [M + H]⁺ ++guanidinocarbonyl]-thiazol-2-yl}-3,4- difluoro-benzamide 7N-{4-[N′-(1H-Benzoimidazol-2-yl)- 423 424 [M + H]⁺ ++guanidinocarbonyl]-thiazol-2-yl}-4-fluoro- benzamide 8N-{4-[N′-(1H-Benzoimidazol-2-yl)- 473 474 [M + H]⁺ +++guanidinocarbonyl]-oxazol-2-yl}-2- trifluoromethoxy-benzamide 92-(2-Trifluoromethoxy-benzoylamino)- 453 454 [M + H]⁺ +thiazole-4-carboxylic acid (4- dimethylamino-[1,3,5]triazin-2-yl)-amide10 N-{4-[N′-(1H-Benzoimidazol-2-yl)- 483 484 [M + H]⁺ ++guanidinocarbonyl]-thiazol-2-yl}-4-bromo- benzamide 11N-{4-[N′-(1H-Benzoimidazol-2-yl)- 435 436 [M + H]⁺ ++guanidinocarbonyl]-thiazol-2-yl}-2- methoxy-benzamide 12N-{4-[N′-(1H-Benzoimidazol-2-yl)- 489 490 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-2- trifluoromethoxy-benzamide 13N-(1H-Benzoimidazol-2-yl)-N′-{2-[4-(2- 558 559 [M + H]⁺ +trifluoromethoxy-benzoyl)-piperazin-1-yl]-thiazole-4-carbonyl}-guanidine 14 N-(1H-Benzoimidazol-2-yl)-N′-[2-(2,3-420 421 [M + H]⁺ + dihydro-benzo[1,4]dioxin-2-yl)-thiazole-4-carbonyl]-guanidine 15 2-Methoxy-N-{4-[4-(3-trifluoromethyl- 490 491[M + H]⁺ +++ phenyl)-piperazine-1-carbonyl]-thiazol-2- yl}-benzamide 163-Fluoro-4-trifluoromethyl-N-(1-{4-[4-(3- 643 644 [M + H]⁺ ++trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}piperidin-4- ylmethyl)-benzamide 173-Cyclopentyl-N-(1-{4-[4-(3- 577 578 [M + H]⁺ ++trifluoromethyl-phenyl)-piperazine-1- carbonyl]-thiazol-2-yl}-piperidin-4ylmethyl)-propionamide 18 2-Trifluoromethoxy-N-(1-{4-[4-(3- 641 642[M + H]⁺ ++ trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin- 4ylmethyl)-benzamide 194-Cyano-N-(1-{4-[4-(3-trifluoromethyl- 582 583 [M + H]⁺ ++phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-4-ylmethyl)-benzamide 20[4-(3-Trifluoromethyl-phenyl)-piperazin-1- 569 570 [M + H]⁺ ++yl]-{2-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-thiazol-4-yl}-methanone 21{2-[4-(4-Trifluoromethoxy-phenyl)- 585 586 [M + H]⁺ +piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 22{2-[4-(2-Trifluoromethoxy-benzyl)- 599 600 [M + H]⁺ +++piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 23{2-[4-(4-Bromo-benzyl)-piperazin-1-yl]- 593 594 [M + H]⁺ +++thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone24 {2-[4-(3-Trifluoromethoxy-benzyl)- 599 600 [M + H]⁺ +++piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 252-(2-Trifluoromethoxy-benzoylamino)- 475 476 [M + H]⁺ +++thiazole-4-carboxylic acid (5,6-dimethyl- 1H-benzoimidazol-2-yl)-amide26 2-(3-Fluoro-4-trifluoromethyl- 536 537 [M + H]⁺ +++benzoylamino)-oxazole-4-carboxylic acid ethyl ester 27N-{4-[N′-(1H-Benzoimidazol-2-yl)- 475 476 [M + H]⁺ +++guanidinocarbonyl]-oxazol-2-yl}-3-fluoro- 4-trifluoromethyl-benzamide 28N-{4-[N′-(1H-Benzoimidazol-2-yl)- 473 474 [M + H]⁺ +++guanidinocarbonyl]-oxazol-2-yl}-2- trifluoromethoxy-benzamide 29{2-[1-(2,5-Dimethoxy-phenyl)-piperidin-4- 560 561 ++yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 30 N-(1H-Benzoimidazol-2-yl)-N′-[2-(4-460 461 [M + H]⁺ +++ benzyl-piperazin-1-yl)-thiazole-4-carbonyl]-guanidine 31 2-(2-Trifluoromethoxy-benzoylamino)- 447 448 [M +H]⁺ +++ thiazole-4-carboxylic acid (1H- benzoimidazol-2-yl)-amide 322-Trifluoromethoxy-N-{4-[4-(3- 544 545 [M + H]⁺ +++trifluoromethyl-phenyl)-piperazine-1- carbonyl]-thiazol-2-yl}-benzamide33 3-Cyclopentyl-N-{4-[4-(3-trifluoromethyl- 480 481 [M + H]⁺ +++phenyl)-piperazine-1-carbonyl]-thiazol-2- yl}-propionamide 343-Fluoro-4-trifluoromethyl-N-{4-[4-(3- 546 547 [M + H]⁺ +++trifluoromethyl-phenyl)-piperazine-1- carbonyl]-thiazol-2-yl}-benzamide35 {2-[1-(3,3-Diphenyl-propyl)-piperidin-4- 618 619 [M + H]⁺ +++yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 36N-(1H-Benzoimidazol-2-yl)-N′-{2-[1-(2- 557 558 [M + H]⁺ +++trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-carbonyl}-guanidine 37 3-Cyclopentyl-1-(4-{4-[4-(3- 549 550[M + H]⁺ +++ trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperazin-1-yl)- propan-1-one 38{2-[4-(2-Methoxy-benzoyl)-piperazin-1- 559 560 [M + H]⁺ +++yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 39 {2-[4-(2-Trifluoromethoxy-benzoyl)-613 614 [M + H]⁺ +++ piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 402-(2-Trifluoromethoxy-benzoylamino)- 459 460 [M + H]⁺ +++oxazole-4-carboxylic acid (5,6-dimethyl- 1H-benzoimidazol-2-yl)-amide 41N-{4-[4-(3,4-Dichloro-phenyl)-piperazine- 544 545 [M + H]⁺ +++1-carbonyl]-thiazol-2-yl}-2- trifluoromethoxy-benzamide 422-(2-Trifluoromethoxy-benzoylamino)- 562 563 [M + H]⁺ +++thiazole-4-carboxylic acid [6-(4-methyl-piperazin-1-yl)-benzothiazol-2-yl]-amide 432-(2-Trifluoromethoxy-benzoylamino)- 492 493 [M + H]⁺ +++thiazole-4-carboxylic acid (5-nitro-1H- benzoimidazol-2-yl)-amide 44N-{4-[4-(2-Methoxy-phenyl)-piperazine-1- 506 507 [M + H]⁺ ++carbonyl]-thiazol-2-yl}-2-trifluoromethoxy- benzamide 45N-{4-[N′-(1H-Benzoimidazol-2-yl)- 487 488 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-2- cyclohexyl-benzamide 462-(2-Trifluoromethoxy-benzoylamino)- 461 462 [M + H]⁺ +++thiazole-4-carboxylic acid (1-methyl-1H- benzoimidazol-2-yl)-amide 472-(2-Trifluoromethoxy-benzoylamino)- 553 554 [M + H]⁺ +++thiazole-4-carboxylic acid [5-(propane-1-sulfonyl)-1H-benzoimidazol-2-yl]-amide 48 {4-[1-(4-Fluoro-benzyl)-1H-692 693 [M + H]⁺ +++ benzoimidazol-2-yl]-piperazin-1-yl}-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4- yl]-thiazol-4-yl}-methanone 49N-(1H-Benzoimidazol-2-yl)-N′-(2- 371 372 [M + H]⁺ +++morpholin-4-yl-thiazole-4-carbonyl)- guanidine 50N-{5-[N′-(1H-Benzoimidazol-2-yl)- 489 490 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-2- trifluoromethoxy-benzamide 51N-{4-[N′-(1H-Benzoimidazol-2-yl)- 473 474 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-4- trifluoromethyl-benzamide 522-[1-(2-Trifluoromethoxy-benzoyl)- 621 622 [M + H]⁺ +++piperidin-4-yl]-thiazole-4-carboxylic acid[5-(propane-1-sulfonyl)-1H-benzoimidazol- 2-yl]-amide 53N-{4-[N′-(1H-Benzoimidazol-2-yl)- 491 492 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-2-fluoro- 4-trifluoromethyl-benzamide54 1-{4-[N′-(1H-Benzoimidazol-2-yl)- 504 505 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-3-(2- trifluoromethoxy-phenyl)-urea 551-(2-Trifluoromethoxy-phenyl)-3-{4-[4-(3- 559 560 [M + H]⁺ +++trifluoromethyl-phenyl)-piperazine-1- carbonyl]-thiazol-2-yl}-urea 56N-{4-[N′-(1H-Benzoimidazol-2-yl)- 491 492 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-3-fluoro- 4-trifluoromethyl-benzamide57 N-{4-[N′-(1H-Benzoimidazol-2-yl)- 441 442 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}-2,6- difluoro-benzamide 58N-[4-(4-Benzhydryl-piperazine-1- 566 567 [M + H]⁺ ++carbonyl)-thiazol-2-yl]-2-trifluoromethoxy- benzamide 59{2-[4-(3,5-Bis-trifluoromethyl-benzoyl)- 665 666 [M + H]⁺ +piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 60{2-[4-(3-Fluoro-4-trifluoromethyl- 615 616 [M + H]⁺ +++benzoyl)-piperazin-1-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 614-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 554 555 [M + H]⁺ +++piperazine-1-carbonyl]-thiazol-2-yl}-piperazine-1-carbonyl)-benzonitrile 624-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 540 541 [M + H]⁺ +++piperazine-1-carbonyl]-thiazol-2-yl}-piperazine-1-ylmethyl)-benzonitrile 634-{4-[4-(3-Trifluoromethyl-phenyl)- 525 526 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperazine-1-carboxylic acidtert-butyl ester 64 (2-Piperazin-1-yl-thiazol-4-yl)-[4-(3- 425 426 [M +H]⁺ + trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 65{2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]- 531 532 [M + H]⁺ ++thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone66 1-[4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 543 544 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperazin-1-yl)-phenyl]-ethanone67 [4-(3-Trifluoromethyl-phenyl)-piperazin-1- 569 570 [M + H]⁺ +yl]-{2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-thiazol-4-yl}-methanone 68[2-(4-Phenyl-piperazin-1-yl)-thiazol-4-yl]- 501 502 [M + H]⁺ +[4-(3-trifluoromethyl-phenyl)-piperazin-1- yl]-methanone 69{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]- 519 520 [M + H]⁺ ++thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone70 4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 553 554 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-benzonitrile 71(4-Benzhydryl-piperazin-1-yl)-[2-(4- 537 538 [M + H]⁺ +++benzyl-piperazin-1-yl)-thiazol-4-yl]- methanone 72[2-(4-Benzyl-piperazin-1-yl)-thiazol-4-yl]- 515 516 [M + H]⁺ +++[4-(3-trifluoromethyl-phenyl)-piperazin-1- yl]-methanone 734-{4-[4-(3-Trifluoromethyl-phenyl)- 543 544 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acidphenyl amide 74 4-{4-[4-(3-Trifluoromethyl-phenyl)- 619 620 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(7-fluoro-2,3- dihydro-benzo[1,4]dioxin-5-yl)-amide 754-{4-[4-(3-Trifluoromethyl-phenyl)- 601 602 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(2,3-dihydro- benzo[1,4]dioxin-6-yl)-amide 764-{4-[4-(3-Trifluoromethyl-phenyl)- 615 616 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(5-methyl-2- trifluoromethyl-furan-3-yl)-amide 774-{4-[4-(3-Trifluoromethyl-phenyl)- 577 578 [M + H]⁺ +++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(2-thiophen-2- yl-ethyl)-amide 78 4-{4-[4-(3-Trifluoromethyl-phenyl)-509 510 [M + H]⁺ + piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carboxylic acid isopropylamide 794-{4-[4-(3-Trifluoromethyl-phenyl)- 627 628 [M + H]⁺ +++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid (2-trifluoromethoxy-phenyl)-amide 80 4-{4-[4-(3-Trifluoromethyl-phenyl)-573 574 [M + H]⁺ + piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carboxylic acid (3-methoxy- phenyl)-amide 814-{4-[4-(3-Trifluoromethyl-phenyl)- 633 634 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(3,4,5- trimethoxy-phenyl)-amide 82 N-{4-[N′-(1H-Benzoimidazol-2-yl)-489 490 [M + H]⁺ +++ guanidinocarbonyl]-thiazol-2-yl}-2-trifluoromethoxy-benzamide 83 2-[1-(2-Trifluoromethoxy-benzoyl)- 508 509[M + H]⁺ + piperidin-4-yl]-thiazole-4-carboxylic acid(4-amino-6-oxo-1,6-dihydro-pyrimidin-2- yl)-amide 842-[1-(2-Trifluoromethoxy-benzoyl)- 556 557 [M + H]⁺ +piperidin-4-yl]-thiazole-4-carboxylic acid(5-benzyl-4H-[1,2,4]triazol-3-yl)-amide 852-[1-(2-Trifluoromethoxy-benzoyl)- 536 537 [M + H]⁺ +piperidin-4-yl]-thiazole-4-carboxylic acid(2-dimethylamino-6-oxo-1,6-dihydro- pyrimidin-4-yl)-amide 862-[1-(2-Trifluoromethoxy-benzoyl)- 507 508 [M + H]⁺ +piperidin-4-yl]-thiazole-4-carboxylic acid(4-methyl-6-oxo-1,6-dihydro-pyrimidin-2- yl)-amide 872-[1-(2-Trifluoromethoxy-benzoyl)- 621 622 [M + H]⁺ +++piperidin-4-yl]-thiazole-4-carboxylic acid[5-(propane-1-sulfonyl)-1H-benzoimidazol- 2-yl]-amide 882-[1-(2-Trifluoromethoxy-benzoyl)- 521 522 [M + H]⁺ +piperidin-4-yl]-thiazole-4-carboxylic acid(4-dimethylamino-[1,3,5]triazin-2-yl)- amide 892-[1-(2-Trifluoromethoxy-benzoyl)- 481 482 [M + H]⁺ +piperidin-4-yl]-thiazole-4-carboxylic acid(5-amino-1H-[1,2,4]triazol-3-yl)-amide 90N-Cyano-N′-{2-[1-(2-trifluoromethoxy- 466 467 [M + H]⁺ +benzoyl)-piperidin-4-yl]-thiazole-4- carbonyl}-guanidine 91N-(1H-Benzoimidazol-2-yl)-N′-(2- 371 372 [M + H]⁺ +morpholin-4-yl-thiazole-4-carbonyl)- guanidine 924-{4-[N′-Acetyl-N″-(1-acetyl-1H- 553 554 [M + H]⁺ +++benzoimidazol-2-yl)-guanidinocarbonyl]-thiazol-2-yl}-piperidine-1-carboxylic acid tert-butyl ester 93N-(1H-Benzoimidazol-2-yl)-N′-[2-(1- 563 564 [M + H]⁺ +diphenylacetyl-piperidin-4-yl)-thiazole-4- carbonyl]-guanidine 94N-(1H-Benzoimidazol-2-yl)-N′-(2- 369 370 [M + H]⁺ +piperidin-4-yl-thiazole-4-carbonyl)- guanidine 954-{4-[N′-(1H-Benzoimidazol-2-yl)- 469 470 [M + H]⁺ +++guanidinocarbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acidtert-butyl ester 96 [4-(1H-Benzoimidazol-2-yl)-piperazin-1- 618 619 [M +H]⁺ +++ yl]-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}-methanone 97[4-(5-Methoxy-1H-benzoimidazol-2-yl)- 583 584 [M + H]⁺ +piperazin-1-yl]-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}- methanone 98{4-[1-(4-Fluoro-benzyl)-1H- 692 693 [M + H]⁺ +++benzoimidazol-2-yl]-piperazin-1-yl}-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4- yl]-thiazol-4-yl}-methanone 993-Fluoro-4-trifluoromethyl-N-(1-{4-[4-(3- 642 643 [M + H]⁺ +trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-4- ylmethyl)-benzamide 1003-Cyclopentyl-N-(1-{4-[4-(3- 576 577 [M + H]⁺ +trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-4- ylmethyl)-propionamide 1012-Trifluoromethoxy-N-(1-{4-[4-(3- 640 641 [M + H]⁺ +trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-4- ylmethyl)-benzamide 1024-Cyano-N-(1-{4-[4-(3-trifluoromethyl- 581 582 [M + H]⁺ +phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-4-ylmethyl)-benzamide 1032-{5-Methyl-2-[1-(2-trifluoromethoxy- 640 641 [M + H]⁺ ++benzoyl)-piperidin-4-yl]-thiazol-4-yl}-1-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- ethanone 104N-(1H-Benzoimidazol-2-yl)-N′-{2-[1-(2- 557 558 [M + H]⁺ +++trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-carbonyl}-guanidine 105 2-[1-(2-Trifluoromethoxy-benzoyl)-515 516 [M + H]⁺ + piperidin-4-yl]-thiazole-4-carboxylic acid(1H-benzoimidazol-2-yl)-amide 106N-(5,6-Dimethyl-1H-benzoimidazol-2-yl)- 571 572 [M + H]⁺ +2-{5-methyl-2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}- acetamide 107[2-(1-Pyridin-4-ylmethyl-piperidin-4-yl)- 515 516 [M + H]⁺ +thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone108 [2-(1-Pyridin-3-ylmethyl-piperidin-4-yl)- 446 447 [M + H]⁺ +thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone109 {2-[1-(2-Trifluoromethoxy-benzyl)- 598 599 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 1102-[1-(2-Trifluoromethoxy-benzoyl)- 647 648 [M + H]⁺ +piperidin-4-yl]-thiazole-4-carboxylic acid bis-(4-chloro-benzyl)-amide111 (4-Benzotriazol-1-yl-piperidin-1-yl)-{2-[1- 584 585 [M + H]⁺ +(2-trifluoromethoxy-benzoyl)-piperidin-4- yl]-thiazol-4-yl}-methanone112 4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 525 526 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidin-1-yl)-benzonitrile 1134-{4-[4-(3-Trifluoromethyl-phenyl)- 468 469 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid 1144-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 568 569 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-benzonitrile 115{2-[1-(3-Trifluoromethoxy-benzyl)- 598 599 [M + H]⁺ ++piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 116{2-[1-(2,5-Dimethoxy-phenyl)-piperidin-4- 560 560 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 117 {2-[1-(4-Methanesulfonyl-phenyl)-578 579 [M + H]⁺ + piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 118[4-(3-Trifluoromethyl-phenyl)-piperazin-1- 569 570 [M + H]⁺ +yl]-[2-(4′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)- thiazol-4-yl]-methanone 119[2-(1-Phenyl-piperidin-4-yl)-thiazol-4-yl]- 500 501 [M + H]⁺ +[4-(3-trifluoromethyl-phenyl)-piperazin-1- yl]-methanone 120[2-(1-Benzyl-piperidin-4-yl)-thiazol-4-yl]- 509 510 [M + H]⁺ +[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)- piperazin-1-yl]-methanone 121{2-[1-(4-Bromo-benzyl)-piperidin-4-yl]- 587 588 [M + H]⁺ +thiazol-4-yl}-[4-(4,6-dimethoxy- [1,3,5]triazin-2-yl)-piperazin-1-yl]-methanone 122 [2-(1-Pyrazin-2-yl-piperidin-4-yl)-thiazol- 502 503 [M +H]⁺ + 4-yl]-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone 123[2-(3,4,5,6-Tetrahydro-2H- 501 502 [M + H]⁺ ++[1,2′]bipyridinyl-4-yl)-thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 124(4-{4-[4-(2-Methylsulfanyl-pyrimidin-4- 592 593 [M + H]⁺ +yl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-(2-trifluoromethoxy- phenyl)-methanone 1254-[4-(3-Trifluoromethyl-phenyl)- 441 442 [M + H]⁺ +piperazine-1-carbonyl]-piperidine-1- carboxylic acid tert-butyl ester126 1-(4-{4-[4-(4,6-Dimethoxy-[1,3,5]triazin-2- 555 556 [M + H]⁺ +yl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-2-(4-fluoro-phenyl)- ethanone 127[4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 607 608 [M + H]⁺ +piperazin-1-yl]-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}- methanone 1281-[4-(3-Chloro-phenyl)-piperazin-1-yl]-2- 606 607 [M + H]⁺ +++{5-methyl-2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}- ethanone 129(4-{4-[4-(7H-Purin-6-yl)-piperazine-1- 586 587 [M + H]⁺ +carbonyl]-thiazol-2-yl}-piperidin-1-yl)-(2-trifluoromethoxy-phenyl)-methanone 130(4-{4-[4-(2,6-Dimethoxy-pyrimidin-4-yl)- 606 607 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-(2-trifluoromethoxy- phenyl)-methanone 1312-{1-[2-(4-Fluoro-phenyl)-acetyl]- 491 492 [M + H]⁺ +piperidin-4-yl}-thiazole-4-carboxylic acid(5,6-dimethyl-1H-benzoimidazol-2-yl)- amide 1322-{1-[5-(4-Chloro-phenyl)-2- 627 628 [M + H]⁺ +trifluoromethyl-furan-3-carbonyl]- piperidin-4-yl}-thiazole-4-carboxylicacid (5,6-dimethyl-1H-benzoimidazol-2-yl)- amide 1332-[1-(2-Trifluoromethoxy-benzoyl)- 543 544 [M + H]⁺ +++piperidin-4-yl]-thiazole-4-carboxylic acid(5,6-dimethyl-1H-benzoimidazol-2-yl)- amide 1344-{4-[4-(3-Trifluoromethyl-phenyl)- 543 544 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acidphenylamide 135 4-{4-[4-(3-Trifluoromethyl-phenyl)- 619 620 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(7-fluoro-2,3- dihydro-benzo[1,4]dioxin-5-yl)-amide 1364-{4-[4-(3-Trifluoromethyl-phenyl)- 601 602 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(2,3-dihydro- benzo[1,4]dioxin-6-yl)-amide 1374-{4-[4-(3-Trifluoromethyl-phenyl)- 615 616 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(5-methyl-2- trifluoromethyl-furan-3-yl)-amide 1384-{4-[4-(3-Trifluoromethyl-phenyl)- 577 578 [M + H]⁺ +++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(2-thiophen-2- yl-ethyl)-amide 139 4-{4-[4-(3-Trifluoromethyl-phenyl)-509 510 [M + H]⁺ + piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carboxylic acid isopropylamide 1404-{4-[4-(3-Trifluoromethyl-phenyl)- 627 628 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid (2-trifluoromethoxy-phenyl)-amide 141 4-{4-[4-(3-Trifluoromethyl-phenyl)-573 574 [M + H]⁺ + piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carboxylic acid (3-methoxy- phenyl)-amide 1424-{4-[4-(3-Trifluoromethyl-phenyl)- 561 562 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(3-fluoro- phenyl)-amide 143 4-{4-[4-(3-Trifluoromethyl-phenyl)- 561 562[M + H]⁺ + piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylicacid (4-fluoro- phenyl)-amide 144 2-Piperidin-4-yl-thiazole-4-carboxylicacid 355 356 [M + H]⁺ + (5,6-dimethyl-1H-benzoimidazol-2-yl)- amide 1452-[1-(2-Trifluoromethoxy-benzoyl)- 556 557 [M + H]⁺ +piperidin-4-yl]-thiazole-4-carboxylic acid[1-(1H-indol-2-yl)-ethyl]-methyl-amide 146(2-Phenyl-morpholin-4-yl)-{2-[1-(2- 545 546 [M + H]⁺ +trifluoromethoxy-benzoyl)-piperidin-4-yl]- thiazol-4-yl}-methanone 1472-[1-(2-Trifluoromethoxy-benzoyl)- 602 603 [M + H]⁺ +piperidin-4-yl]-thiazole-4-carboxylic acidmethyl-(2-morpholin-4-yl-1-phenyl-ethyl)- amide 1482-[1-(2-Trifluoromethoxy-benzoyl)- 533 534 [M + H]⁺ ++piperidin-4-yl]-thiazole-4-carboxylic acidbenzyl-(2-hydroxy-ethyl)-amide 149 2-[1-(2-Trifluoromethoxy-benzoyl)-593 594 [M + H]⁺ + piperidin-4-yl]-thiazole-4-carboxylic acidbenzyl-phenethyl-amide 150 [1-(5-Chloro-2-methylamino-phenyl)-3,4- 654655 [M + H]⁺ ++ dihydro-1H-isoquinolin-2-yl]-{2-[1-(2-trifluoromethoxy-benzoyl)-piperidin-4-yl]- thiazol-4-yl}-methanone 151(4-{4-[4-(3-Chloro-phenyl)-piperazine-1- 578 579 [M + H]⁺ +carbonyl]-thiazol-2-yl}-piperidin-1-yl)-(2-trifluoromethoxy-phenyl)-methanone 152[4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 419 420 [M + H]⁺ ++piperazin-1-yl]-(2-piperidin-4-yl-thiazol-4- yl)-methanone 153{2-[1-(2,4-Dimethoxy-phenyl)-piperidin-4- 560 561 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 154 {2-[1-(4-Trifluoromethoxy-phenyl)-584 585 [M + H]⁺ + piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 155[4-(3-Trifluoromethyl-phenyl)-piperazin-1- 568 569 [M + H]⁺ +yl]-{2-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-thiazol-4-yl}-methanone 156[2-(1-Benzo[1,3]dioxol-5-yl-piperidin-4- 544 545 [M + H]⁺ +yl)-thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 157{2-[1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)- 558 559 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 158{2-[1-(2-Methoxy-phenyl)-piperidin-4-yl]- 530 531 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone159 {2-[1-(3,4-Dimethoxy-phenyl)-piperidin-4- 560 561 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 1601-{4-[4-(6,7-Dihydroxy-3,4-dihydro-1H- 495 496 [M + H]⁺ +isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro-phenyl)- ethanone 1611-{4-[4-(6,7-Dimethoxy-3,4-dihydro-1H- 523 524 [M + H]⁺ +isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro-phenyl)- ethanone 1621-{4-[4-(2,3-Dihydro-indole-1-carbonyl)- 449 450 [M + H]⁺ +thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro- phenyl)-ethanone 1631-{4-[4-(3,4-Dihydro-1H-isoquinoline-2- 463 464 [M + H]⁺ +carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2- (4-fluoro-phenyl)-ethanone164 {2-[1-(2,6-Dimethoxy-pyrimidin-4-yl)- 562 563 [M + H]⁺ ++piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 165{2-[1-(2-Bromo-benzyl)-piperidin-4-yl]- 592 593 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone166 4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 539 540 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidin-1-ylmethyl)-benzonitrile167 [2-(1-Biphenyl-4-ylmethyl-piperidin-4-yl)- 590 591 [M + H]⁺ +thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone168 {2-[1-(2,6-Difluoro-benzyl)-piperidin-4-yl]- 550 551 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone169 {2-[1-(4-Trifluoromethyl-benzyl)-piperidin- 582 583 [M + H]⁺ +4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 170{2-[1-(4-Fluoro-benzyl)-piperidin-4-yl]- 532 533 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone171 {2-[1-(2-Chloro-4-fluoro-benzyl)-piperidin- 566 567 [M + H]⁺ +4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 172 {2-[1-(4-Trifluoromethoxy-benzyl)-598 599 [M + H]⁺ + piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 173{2-[1-(3-Methoxy-benzyl)-piperidin-4-yl]- 544 545 +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- [M + H]⁺piperazin-1-yl]-methanone 174 {2-[1-(4-Bromo-benzyl)-piperidin-4-yl]-592 593 [M + H]⁺ + thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 175 {2-[1-(3,5-Bis-trifluoromethyl-benzyl)-650 651 [M + H]⁺ + piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 176{2-[1-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)- 563 564 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 177[2-(1-Benzyl-piperidin-4-yl)-thiazol-4-yl]- 514 515 [M + H]⁺ +[4-(3-trifluoromethyl-phenyl)-piperazin-1- yl]-methanone 178{2-[1-(3-Methoxy-phenyl)-piperidin-4-yl]- 530 531 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone179 2-(2-{1-[2-(4-Fluoro-phenyl)-acetyl]- 537 538 [M + H]⁺ +piperidin-4-yl}-thiazole-4-carbonyl)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3- carboxylic acid methyl ester180 2-(4-Fluoro-phenyl)-1-{4-[4-(4-phenyl- 492 493 [M + H]⁺ +piperazine-1-carbonyl)-thiazol-2-yl]- piperidin-1-yl}-ethanone 1812-(4-Fluoro-phenyl)-1-(4-{4-[4-(5- 600 601 [M + H]⁺ +trifluoromethyl-benzotriazol-1-yl)-piperidine-1-carbonyl]-thiazol-2-yl}- piperidin-1-yl)-ethanone 1821-{4-[4-(4-Benzotriazol-1-yl-piperidine-1- 532 533 [M + H]⁺ +carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2- (4-fluoro-phenyl)-ethanone183 2-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 573 574 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carbonyl)-nicotinicacid 184 2-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 616 617 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-terephthalic acid 1852-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 572 573 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carbonyl)-benzoicacid 186 3-Hydroxy-2-(4-{4-[4-(3-trifluoromethyl- 588 589 [M + H]⁺ +phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-benzoic acid 1874,5-Dichloro-2-(4-{4-[4-(3-trifluoromethyl- 640 641 [M + H]⁺ +phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-benzoic acid 1882-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 562 563 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-cyclopent-1- enecarboxylic acid 1892-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 578 579 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carbonyl)-cyclohexanecarboxylic acid 190 2-(4-{4-[4-(3-Trifluoromethyl-phenyl)-576 577 [M + H]⁺ + piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-carbonyl)-cyclohex-1- enecarboxylic acid 1914-Oxo-4-(4-{4-[4-(3-trifluoromethyl- 522 523 [M + H]⁺ +phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-but-2-enoic acid 192{2-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)- 583 584 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 193[2-(1-Pentafluorobenzenesulfonyl- 654 655 [M + H]⁺ +piperidin-4-yl)-thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 194{2-[1-(Thiophene-2-sulfonyl)-piperidin-4- 570 571 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 195{2-[1-(2-Chloro-4-fluoro-benzenesulfonyl)- 616 617 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 196{2-[1-(2-Bromo-benzenesulfonyl)- 642 643 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 197{2-[1-(6-Chloro-imidazo[2,1-b]thiazole-5- 644 645 [M + H]⁺ +sulfonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 198[2-(1-Phenylmethanesulfonyl-piperidin-4- 578 579 [M + H]⁺ +yl)-thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 199 {2-[1-(4-Bromo-benzenesulfonyl)-642 643 [M + H]⁺ + piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 200{2-[1-(2,4-Dichloro-benzenesulfonyl)- 632 633 [M + H]⁺ ×piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 201{2-[1-(3,5-Bis-trifluoromethyl- 700 701 [M + H]⁺ ++benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone 202{2-[1-(5-Chloro-2-methoxy- 628 629 [M + H]⁺ ++benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone 203{2-[1-(5-Bromo-thiophene-2-sulfonyl)- 648 649 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 204{2-[1-(Toluene-4-sulfonyl)-piperidin-4-yl]- 578 579 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone205 {2-[1-(4-Trifluoromethoxy- 648 649 [M + H]⁺ +benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone 206{2-[1-(4-Chloro-benzenesulfonyl)- 598 599 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 207N-[4-(4-{4-[4-(3-Trifluoromethyl-phenyl)- 621 622 [M + H]⁺ +piperazine-1-carbonyl]-thiazol-2-yl}-piperidine-1-sulfonyl)-phenyl]-acetamide 208[2-(1-Benzenesulfonyl-piperidin-4-yl)- 564 565 [M + H]⁺ +thiazol-4-yl]-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone209 {2-[1-(3-Methoxy-benzoyl)-piperidin-4-yl]- 558 559 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone210 {2-[1-(4-Methyl-3,4-dihydro-2H- 599 600 [M + H]⁺ ++benzo[1,4]oxazine-7-carbonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 211{2-[1-(Quinoxaline-6-carbonyl)-piperidin- 580 581 [M + H]⁺ +4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 212{2-[1-(Thiophene-2-carbonyl)-piperidin-4- 534 535 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 213{2-[1-(Benzo[b]thiophene-2-carbonyl)- 584 585 [M + H]⁺ ++piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 2143-Phenyl-1-(4-{4-[4-(3-trifluoromethyl- 554 555 [M + H]⁺ ++phenyl)-piperazine-1-carbonyl]-thiazol-2- yl}-piperidin-1-yl)-propenone215 {2-[1-(3-Fluoro-4-trifluoromethyl- 614 615 [M + H]⁺ +++benzoyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 216{2-[1-(5-tert-Butyl-2-methyl-2H-pyrazole- 588 589 [M + H]⁺ ++3-carbonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1- yl]-methanone 217{2-[1-(2,3-Dihydro-benzo[1,4]dioxine-2- 586 587 [M + H]⁺ +++carbonyl)-piperidin-4-yl]-thiazol-4-yl}[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 218(2-{1-[5-(4-Chloro-phenyl)-2- 696 697 [M + H]⁺ +++trifluoromethyl-furan-3-carbonyl]- piperidin-4-yl}-thiazol-4-yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 219{2-[1-(3,5-Dimethyl-isoxazole-4-carbonyl)- 547 548 [M + H]⁺ +piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 220(2-{1-[4-(4-Chloro-benzenesulfonyl)-3- 722 723 [M + H]⁺ +methyl-thiophene-2-carbonyl]-piperidin-4-yl}-thiazol-4-yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 221{2-[1-(4-Methyl-[1,2,3]thiadiazole-5- 550 551 [M + H]⁺ +carbonyl)-piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 222{2-[1-(Pyridine-3-carbonyl)-piperidin-4- 529 530 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 223{2-[1-(2-Trifluoromethoxy-benzoyl)- 612 613 [M + H]⁺ +++piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 2243-Cyclopentyl-1-(4-{4-[4-(3- 548 549 [M + H]⁺ +trifluoromethyl-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)- propan-1-one 225[4-(3-Trifluoromethyl-phenyl)-piperazin-1- 618 619 [M + H]⁺ +yl]-{2-[1-(3,4,5-trimethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}-methanone 226{2-[1-(3-Dimethylamino-benzoyl)- 571 572 [M + H]⁺ ++piperidin-4-yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]- methanone 227[2-(2-{1-[2-(4-Fluoro-phenyl)-acetyl]- 535 536 [M + H]⁺ +piperidin-4-yl}-thiazole-4-carbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-acetic acid methyl ester 2281-(2-{1-[2-(4-Fluoro-phenyl)-acetyl]- 516 517 [M + H]⁺ +piperidin-4-yl}-thiazole-4-carbonyl)-4- phenyl-piperidine-4-carbonitrile229 2-(4-Fluoro-phenyl)-1-(4-{4-[4-(2- 511 523 [M + H]⁺ +methoxy-phenyl)-piperazine-1-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-ethanone 230{2-[1-(Furan-2-carbonyl)-piperidin-4-yl]- 518 519 [M + H]⁺ +thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]-methanone231 1-{4-[4-(4-Butyl-piperazine-1-carbonyl)- 472 473 [M + H]⁺ +thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro- phenyl)-ethanone 2321-{4-[4-(6,7-Dimethoxy-3-methyl-3,4- 537 538 [M + H]⁺ +dihydro-1H-isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro- phenyl)-ethanone 2331-{4-[4-(6,7-Dihydroxy-1-methyl-3,4- 509 510 [M + H]⁺ +dihydro-1H-isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro- phenyl)-ethanone 2341-{4-[4-(6,7-Dimethoxy-1-methyl-3,4- 537 538 [M + H]⁺ +dihydro-1H-isoquinoline-2-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-fluoro- phenyl)-ethanone 2351-(4-{4-[1-(5-Chloro-2-methylamino- 602 603 [M + H]⁺ +phenyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-thiazol-2-yl}-piperidin-1-yl)-2- (4-fluoro-phenyl)-ethanone236 2-(4-Fluoro-phenyl)-1-(4-{4-[2-(4-fluoro- 495 496 [M + H]⁺ +phenyl)-pyrrolidine-1-carbonyl]-thiazol-2- yl}-piperidin-1-yl)-ethanone237 2-(4-Fluoro-phenyl)-1-{4-[4-(4-pyridin-2- 493 494 [M + H]⁺ +yl-piperazine-1-carbonyl)-thiazol-2-yl]- piperidin-1-yl}-ethanone 2381-(4-{4-[4-(3-Chloro-phenyl)-piperazine-1- 526 527 [M + H]⁺ +carbonyl]-thiazol-2-yl}-piperidin-1-yl)-2- (4-fluoro-phenyl)-ethanone239 {2-[1-(2,5-Dimethoxy-phenyl)-piperidin-4- 560 561 [M + H]⁺ +yl]-thiazol-4-yl}-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 2404-{4-[4-(3-Trifluoromethyl-phenyl)- 633 634 [M + H]⁺ ++piperazine-1-carbonyl]-thiazol-2-yl}- piperidine-1-carboxylic acid(3,4,5- trimethoxy-phenyl)-amide ¹⁾The biological data refer to resultsobtained from the NF-κB inflammation assay. [“+” stands for 50-80%inhibition, “++” means 80-90% and “+++” stands for 90-100% inhibition]Proteasome Assay:

The chymotryptic activity of the 20S proteasome (Immatics, Tübingen) wasdetermined using a Tecan Ultra plate reader and Suc-LLVT-AMC assubstrate (Bachem). In the wells of a black 96 well polypropylene plate,2 μl of the respective inhibitor dissolved in DMSO were mixed with 50 μlsubstrate solution (25 mM HEPES pH 7.5 at 20° C., 0.5 mM EDTA andSuc-LLVT-AMC (in the appropriate concentration) and the reaction wasinitiated by adding 150 μl proteasome solution (1.3 μg/ml 20S proteasomein 25 mM HEPES pH 7.5 at 20° C., 0.5 mM EDTA, 0.033% (w/v) SDS).Substrate hydrolysis was followed by fluorescence spectroscopy(excitation wavelength: 360 nm; emission wavelength: 465 nm) for 20 minat 30° C. and initial velocities were calculated and expressed as changein relative fluorescence units (RFU) per second.

For the determination of the IC₅₀ values (concentration of inhibitorrequired for 50% inhibition) at least four different inhibitorconcentrations were applied. Each data point was recorded intriplicates. Curves were fitted with the a suitable program.

The Compounds have average activities between 1 and 30 μM

T-Lymphocyte Proliferation Assay:

Inhibition of Stimulated Peripheral Blood Monocytes (PBMC).

PBMCs were isolated from the blood of healthy volunteers with the helpof ACCUSPIN™ System Histopaque®-1077 tubes, washed and resuspended with10⁶ cells/ml in Dulbecco's modified eagles medium, containing 10% fetalcalf serum and 2 mM Glutamine.

The cells were stimulated with 2 μg/ml phytohemoagglutinin in thepresence of test compound or blank vehicle for 72 h. 4 h prior to theend of the incubation period, 5-bromo-2′-desoxyuridine (BrdU) was addedto label the proliferating cells. After the incubation, the cells wereseparated by centrifugation and the culture supernatant removed.Incorporated BrdU was quantified with the help of an enzyme-linkedimmunosorbent assay.

For the determination of the IC₅₀ values (concentration of inhibitorrequired for 50% inhibition) at least four different inhibitorconcentrations were applied. Each data point was recorded intriplicates. Curves were fitted with the a suitable program.

Influence of Compounds According to the Invention on Proliferation ofT-Cells

Compounds according to Examples 1-24 resulted in an inhibition of morethan 50% compared to control experiments.

The average EC₅₀ of the compounds were between 3 and 40 μM.

Thus, the compounds of formula I are suitable for treating inflammatorydiseases or diseases associated with Tcells.

Inhibition of NF-κB-Induced Inflammation:

For the determination of anti-inflammatory activity of the compounds thePRINCESS® NINA Instant Assay from Cell Culture Service GmBH was used.This assay is based on 30 recombinant A549-NF-κB-SEAP reporter cellspreceded in 96-well flat bottom plates. As the transfected reportergenfor SEAP (secreted embryonic alkaline phosphatase) is undertranscriptional control of a NF-κB-responsive element, the expression ofthis reporter is activated upon stimulation with TNF-α. SEAP secretioninto the culture supernatant can be detected by the chemiluminescentsubstrate CSPD®. Test compounds that inhibit the NF-κB activation showreduced SEAP activity and reduced luminescent readout.

Following 18 h of reactivation at 37° C., 5% CO₂ and 90% relativehumidity, the cells were incubated with 0.01 up to 100 μM of testcompound for 4.5 h before stimulation with 2 ng/ml TNF-α. Afterstimulation with TNF-α for 22 h endogenous phosphatases were inactivatedand CSPD® substrate was supplied for 40 min. SEAP activity then wasquantified by measuring luminescence as relative light units (RLU) usinga Tecan Ultra reader. Each data point was recorded in quadruplicates andEC50 values were calculated via fitting function and the Microsoft ExcelSolver.

1. A compound of the formula (I) and/or a salt thereof,

wherein R¹ independently represents hydrogen, alkyl, cycloalkyl,hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl,heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl;R² independently represents —NR³R⁴,

R³ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, —OH,—SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl orheteroaryl, R⁴ independently represents alkyl, cycloalkyl, alkoxy,alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl orheteroaryl; R⁵ independently represents H, COR⁶, CO₂R⁶, SOR⁶, SO₂R⁶,SO₃R⁶, alkyl, cycloalkyl, alkoxy, —NH₂, alkylamine, —NR⁷COR⁶, halogen,—OH, —SH, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl orheteroaryl; R⁶ independently represents H, alkyl, cycloalkyl, —NH₂,alkylamine, aryl or heteroaryl; R⁷ independently represents H, alkyl,cycloalkyl, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl, aryl, orheteroaryl; p is 0, or 1; q is 0, or 1; X is CO or SO₂; wherein an alkylgroup, if not stated otherwise, denotes a linear or branchedC₁-C₆-alkyl, preferably a linear or branched chain of one to five carbonatoms, a linear or branched C₂-C₆-alkenyl or a linear or branchedC₂-C₆-alkinyl group, which can optionally be substituted by one or moresubstituents R′; wherein R′ independently represents H, —CO₂R″, —CONHR″,—CR″O, —SO₂NR″, —NR″-CO-haloalkyl, —NO₂, —NR″—SO₂-haloalkyl,—NR″—SO₂-alkyl, —SO₂-alkyl, —NR″—CO-alkyl, —CN, alkyl, cycloalkyl,aminoalkyl, alkylamino, alkoxy, —OH, —SH, alkylthio, hydroxyalkyl,hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl orheteroaryl; wherein R″ independently represents H, haloalkyl,hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl or aminoalkyl; whereina cycloalkyl group denotes a non-aromatic ring system containing threeto eight carbon atoms, wherein one or more of the carbon atoms in thering can be substituted by a group E, E being 0, S, SO, SO₂, N, or NR″,R″ being as defined above; wherein an alkoxy group denotes an O-alkylgroup, the alkyl group being as defined above; the alkoxy group ispreferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy group;wherein an alkylthio group denotes an S-alkyl group, the alkyl groupbeing as defined above; wherein an haloalkyl group denotes an alkylgroup which is substituted by one to five halogen atoms, the alkyl groupbeing as defined above; wherein a hydroxyalkyl group denotes an HO-alkylgroup, the alkyl group being as defined above; wherein a haloalkyloxygroup denotes an alkoxy group which is substituted by one to fivehalogen atoms, the alkyl group being as defined above; wherein ahydroxyalkylamino group denotes an (HO-alkyl)₂-N— group orHO-alkyl-NH-group, the alkyl group being as defined above; wherein analkylamino group denotes an HN-alkyl or N-dialkyl group, the alkyl groupbeing as defined above; wherein a halogen group is chlorine, bromine,fluorine or iodine; wherein an aryl group denotes an aromatic grouphaving five to fifteen carbon atoms, which can optionally be substitutedby one or more substituents R′, where R′ is as defined above; wherein aheteroaryl group denotes a 5- or 6-membered heterocyclic group whichcontains at least one heteroatom like O, N, S, wherein said heterocyclicgroup can be fused to another ring and can optionally be substituted byone or more substituents R′, wherein R′ is as defined above.
 2. Thecompound according to claim 1 wherein p=0, q=1, and X═CO.
 3. Thecompound according to claim 1 wherein p=0, q=1, and X═SO₂.
 4. Thecompound according to claim 1 wherein p=1, q=1, and X═CO.
 5. Thecompound according to claim 1 wherein p=1, q=1, and X═SO₂.
 6. A compoundof formula (III), or a salt, or a stereoisomer thereof,

wherein R¹ is —C(O)R⁷, —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸,—C(S)R⁷, or R¹ and R² together with the Z to which they are attachedform a 3 to 8 membered ring, wherein at least one ring atom is aheteroatom like O, N, S and the ring optionally has a substituent R⁹; R²is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, aryl or R² isabsent in the case Z forms a ring together with R¹; R³ is H,C(O)NR^(a)R^(b) halogen, alkyl, haloalkyl, aryl or heteroaryl; R⁴ is H,halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸,—C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl,haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl,alkylaryl, or aryl; R⁵ is H, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸,—(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸,cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or aryl; R^(a) isH, halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸,—C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl,haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl,alkylaryl, or aryl; R^(b) independently represents H, —CN, —OH, —SH,—CO₂R^(4′), —C(O)R^(4′), —SO₂NR^(4′), —NR⁴R^(5′), —C(O)NR⁷R⁸,—SO₂-alkyl, —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),—NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl,—NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heterocycle, alkyl, cycloalkyl,alkylamino, alkoxy, alkylthio, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,—C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,—C(NR^(4″))NR^(4′)benz-oxazolyl, hydroxyalkyl, hydroxycycloalkyl,hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl ora heterocycle; R⁷, R^(7′), R⁸ independently represent H, halogen, alkyl,cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,hydroxyalkylamino, alkylamino, —NHaryl, heteroaryl, alkylaryl, or aryl;A is CO or SO₂; X is NR^(2′), O, S, or CR^(2′); Z is N or CR^(2′); if Zis CH then X is O or NR^(2′) R^(2′) is H, alkyl, —C(O)NR², —C(O)R^(b),cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, or aryl; p is 1 to6; q is 1 to 6; r is 0, or 1; R⁹ independently represents H, —CN, —OH,—SH, —CO₂R^(4′), —C(O)R^(4′), —C(O)NR⁷R⁸, —SO₂NR^(4′), —NR^(4′)R^(5′),—SO₂-alkyl, —SO₂R^(4′), SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″),—NR^(4′)—CO-haloalkyl, —NO₂, —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl,—NR^(4′)—CO-alkyl, —NR^(4′)(CH₂)_(p)heterocycle, alkyl, cycloalkyl,alkylamino, alkoxy, alkylthio, —O(CH₂)_(p)[O(CH₂)_(p]) _(q)OCH₃,—C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,—C(NR^(4″))NR^(4′)benzoxazolyl hydroxyalkyl, hydroxycycloalkyl,hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl ora heterocycle; R^(4′), R^(4″), R^(5′) independently represent H,halogen, alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —CH₂)_(p)NR⁷R⁸,—C(O)NR⁷R⁸, —N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl,haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl,alkylaryl, or aryl wherein an alkyl group, if not stated otherwise,denotes a linear or branched C₁-C₆-alkyl, a linear or branchedC₂-C₆-alkenyl or a linear or branched C₂-C₆-alkynyl group, which can besubstituted by one or more substituents R⁹; R⁹ being defined as above. aheterocycle denotes a heterocycloalkyl group or a heteroaryl group; acycloalkyl group denotes a non-aromatic ring system containing three toeight carbon atoms, wherein one or more of the carbon atoms in the ringcan be substituted by a group R⁹ being as defined above; aheterocycloalkyl group denotes a non-aromatic ring system containing twoto ten carbon atoms and at least one heteroatom like O, N, or S, whereinone or more of the carbon atoms in the ring can be substituted by R⁹being as defined above; an alkoxy group denotes an O-alkyl group, thealkyl group being as defined above; an alkylthio group denotes anS-alkyl group, the alkyl group being as defined above; an haloalkylgroup denotes an alkyl group which is substituted by one to five halogenatoms, the alkyl group being as defined above; a hydroxyalkyl groupdenotes an HO-alkyl group, the alkyl group being as defined above; anhaloalkyloxy group denotes an alkoxy group which is substituted by oneto five halogen atoms, the alkyl group being as defined above; ahydroxyalkylamino group denotes an (HO-alkyl)₂-N— group or HO-alkyl-NH—group, the alkyl group being as defined above; an alkylamino groupdenotes an HN-alkyl or N-dialkyl group, the alkyl group being as definedabove; a halogen group is fluorine, chlorine, bromine, or iodine; anaryl group denotes an aromatic group having five to fifteen carbonatoms, which can be substituted by one or more substituents R⁹, where R⁹is as defined above; a heteroaryl group denotes a 5- to 10-memberedaromatic heterocyclic group which contains at least one heteroatom likeO, N, S, wherein the heterocyclic group may be fused to another ring,and the heterocyclic group or the fused ring can both be substitutedindependently by one or more substituents R⁹, wherein R⁹ is as definedabove; a alkylaryl or arylalkyl group denotes an alkyl group as definedabove, which is bound to an aryl fragment as defined above via a singlebond, wherein the linkage to the central moiety occurs through the alkylpart or the aryl part.
 7. A compound of formula (II), or a salt, or astereoisomer thereof,

wherein R¹ is —C(O)R⁷, —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸,—C(S)R⁷, or R¹ and R² together with the N-atom or the C-atom to whichthey are attached form a 3 to 8 membered ring, wherein at least one ringatom is a heteroatom like O, N, S and the ring optionally has asubstituent R⁹; R² is H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl,hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, arylor R² is absent in the case Z forms a ring together with R¹; R³ is H,halogen, alkyl, haloalkyl, aryl or heteroaryl; R⁶ is H, halogen,—C(O)R⁷, —C(O)CHR⁷R⁸, —C(O)NR⁷R⁸, —C(O)OR⁷, —R⁷C(O)R⁸, —C(S)R^(7′),—C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —(CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸, —N═CR⁷R⁸,—NR⁷C(O)R^(7′), alkyl, cycloalkyl, heterocycloalkyl, haloalkyl,hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, oraryl; R⁷, R^(7′), R⁸ independently represent H, halogen, alkyl,cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl,hydroxyalkylamino, alkylamino, —NHaryl, heteroaryl, alkylaryl, or aryl;A is CO or SO₂; X is NR^(2′), O, S, or CR^(2′); Y is N, O, or CR^(2′); Zis N or CR^(2′); if Z is CH then X is O or NR^(2′) R^(2′) is H, alkyl,—C(O)NR², —C(O)R^(b), cycloalkyl, heterocycloalkyl, haloalkyl,hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, oraryl; n is 0 to 2; p is 1 to 6; q is 1 to 6; r is 0, or 1; R⁹independently represents H, —CN, —OH, —SH, —CO₂R^(4′), —C(O)R^(4′),—C(O)NR⁷R⁸, —SO₂NR^(4′), —NR^(4′)R^(5′), —SO₂-alkyl, —SO₂R^(4′),SO₃R^(4′), —N═CR^(4′)R^(5′), —NR^(4′)C(O)R^(4″), —NR^(4′)—CO-haloalkyl,—NO₂, —NR^(4′)—SO₂-haloalkyl, —NR^(4′)—SO₂-alkyl, —NR^(4′)—CO-alkyl,—NR^(4′)(CH₂)_(p)heterocycle, alkyl, cycloalkyl, alkylamino, alkoxy,alkylthio, —O(CH₂)_(p)[O(CH₂)_(p)]_(q)OCH₃,—C(NR^(4″))NR^(4′)benzimidazolyl, —C(NR^(4″))NR^(4′)benzthiazolyl,—C(NR^(4″))NR^(4′)benzoxazolyl hydroxyalkyl, hydroxycycloalkyl,hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl ora heterocycle; R^(4′), R^(4″), R^(5′) independently are H, halogen,alkyl, —C(NR⁷)NR^(7′)R⁸, —(CH₂)_(p)aryl, —CH₂)_(p)NR⁷R⁸, —C(O)NR⁷R⁸,—N═CR⁷R⁸, —NR⁷C(O)R⁸, cycloalkyl, heterocycloalkyl, haloalkyl,hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, alkylaryl, oraryl; wherein an alkyl group, if not stated otherwise, denotes a linearor branched C₁-C₆-alkyl, a linear or branched C₂-C₆-alkenyl or a linearor branched C₂-C₆-alkynyl group, which can be substituted by one or moresubstituents R⁹; R⁹ being defined as above. a heterocycle denotes aheterocycloalkyl group or a heteroaryl group; a cycloalkyl group denotesa non-aromatic ring system containing three to eight carbon atoms,wherein one or more of the carbon atoms in the ring can be substitutedby a group R⁹ being as defined above; a heterocycloalkyl group denotes anon-aromatic ring system containing two to ten carbon atoms and at leastone heteroatom like O, N, or S, wherein one or more of the carbon atomsin the ring can be substituted by R⁹ being as defined above; an alkoxygroup denotes an O-alkyl group, the alkyl group being as defined above;an alkylthio group denotes an S-alkyl group, the alkyl group being asdefined above; an haloalkyl group denotes an alkyl group which issubstituted by one to five halogen atoms, the alkyl group being asdefined above; a hydroxyalkyl group denotes an HO-alkyl group, the alkylgroup being as defined above; an haloalkyloxy group denotes an alkoxygroup which is substituted by one to five halogen atoms, the alkyl groupbeing as defined above; a hydroxyalkylamino group denotes an(HO-alkyl)₂-N-group or HO-alkyl-NH-group, the alkyl group being asdefined above; an alkylamino group denotes an HN-alkyl or N-dialkylgroup, the alkyl group being as defined above; a halogen group isfluorine, chlorine, bromine, or iodine; an aryl group denotes anaromatic group having five to fifteen carbon atoms, which can besubstituted by one or more substituents R⁹, where R⁹ is as definedabove; a heteroaryl group denotes a 5- to 10-membered aromaticheterocyclic group which contains at least one heteroatom like O, N, S,wherein the heterocyclic group may be fused to another ring and theheterocyclic group or the fused ring can both be substitutedindependently by one or more substituents R⁹, wherein R⁹ is as definedabove; a alkylaryl or arylalkyl group denotes an alkyl group as definedabove, which is bound to an aryl fragment as defined above via a singlebond, wherein the linkage to the central moiety occurs through the alkylpart or the aryl part.
 8. The compound according to claim 6 wherein R²and R³ is H; A is CO; r is 1, and X is O or S.
 9. The compound accordingto claim 6 wherein R⁴ and R³ is H; A is CO; A is CO; r is 1, and X is Oor S, Z forms together with R¹ a 6-membered ring and R² is absent; andif Z is N then X is O or S, or if Z is CR^(2′), X is O.
 10. The compoundaccording to claim 6 wherein R² and R³ is H; A is CO; A is CO; r is 1,and X is O or S, Z is N, le is COR⁷; wherein R⁷ is an optionallysubstituted phenyl and R⁵ is C(NR⁷)N^(7′)R⁸ wherein R⁸ is aheterocycloalkyl.
 11. The compound according to claim 6 wherein Z formstogether with R¹ a 6-membered ring and R² is absent; A is CO; r is 1, Zis N, R³ is H; X is O or S, A is CO and R⁵ is C(NR⁷)NR^(7′)R⁸ wherein R⁸is a heterocycloalkyl.
 12. The compound according to claim 6 wherein Zforms together with R¹ a 6-membered ring and R² is absent; A is CO; A isCO; r is 1, X is O or S, and if Z is N, X is O or S, if Z is CH, X is O.13. The compound according to claim 7 wherein A is CO; X is O or S, A isCO; r is 1, R³ is H and Y is NR^(2′) wherein R^(2′) is optionallysubstituted phenyl.
 14. The compound according to claim 7 wherein A isCO; X is O or S, A is CO; r is 1, R³ is H and Y is NR^(2′) whereinR^(2′) is 3-substituted trifluoromethylphenyl.
 15. A medicamentcomprising a compound according to claim
 1. 16. A composition containinga compound according to claim 1 and a pharmaceutically acceptablecarrier or diluent.